Abstract
The ability of cutaneous malignancies to develop and progress involves a complex interplay with the local immune environment. Multiple immunomodulatory mechanisms underlie the ability of squamous cell carcinoma, basal cell carcinoma and melanoma to evade immune detection. These mechanisms include a modulation of the gene profiles of these cancers, which populations of immune cells are present and which cytokines are produced in the immune microenvironment. With squamous cell carcinoma, the gene expression and cytokine profile show an immunosuppressed microenvironment, along with functionally compromised dendritic cells and tumor-associated macrophages being present in the tumor microenvironment. Basal cell carcinoma also achieves immune evasion with an immunosuppressed microenvironment, as seen by the Th2 dominant cytokine profile and the presence of regulatory T cells. Immunosuppressed transplant patients have increased incidence of and more aggressive non-melanoma skin cancers due to the altered immune microenvironment, with modified T cell populations and ratios and pro-tumoral cytokines. Melanoma, despite its immunogenicity, displays a number of immune suppressive mechanisms, such as impaired antigen-presenting cell maturation, T cell anergy, the induction and recruitment of regulatory T cells and myeloid-derived suppressor cells. The understanding of the immune microenvironment of cutaneous malignancies is crucial, as it affords many potential targets for therapeutic options.
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Keywords
- Basal cell carcinoma
- Squamous cell carcinoma
- Melanoma
- Macrophages
- Regulatory T cells
- Dendritic cells
- Langerhans cells
- Imiquimod
- Th1 immune response
- Th2 immune response
Cutaneous malignancies are the most common human cancers, with basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma comprising the majority of skin cancers. The public health burden of these cancers is significant, with basal cell carcinoma being the most common human cancer, squamous cell carcinoma being the second most common and melanoma being the fifth and sixth most common cancer in men and women respectively [1, 2]. Each year in the US, about 5 million people are treated for skin cancer and the cost of this treatment is approximately 8.1 billion dollars. 2.8 million cases of BCC alone are diagnosed each year in the US [3]. Understanding these cancers and their context within the immune environment can lead to better treatment options and novel therapeutic approaches being developed for the patients diagnosed each year.
The development and progression of these malignancies involves complex interactions with the local immune microenvironment. The tumor microenvironment includes tumor and non-tumor cells at the dynamic interface of neoplasia [4]. The immune cells include Langerhans cells, dermal dendritic cells, CD4 and CD8 T-cells, T-regulatory cells, macrophages, natural killer cells and mast cells. T cells, both CD4 and CD8, and dendritic cells are often shown to be infiltrating various tumors, and tumor-associated macrophages are often found surrounding and infiltrating the tumor as well. These cells, when functioning properly, work both in concert and independently towards immunosurveillance, the prevention of malignant progression and regression of primary malignancies. Immunosuppression, such as in transplant recipients, increases the risk of skin cancer, in particular the non-melanoma skin cancers. Additionally, melanoma behaves more aggressively in immunosuppressed patients. The malignancy’s ability to evade immunosurveillance, progress and metastasize is the result of multiple immunosuppressive mechanisms.
Our understanding of cutaneous cancers’ interaction with the immune environment has grown over recent years and continues to be explored. The attempts to translate these basic science developments into clinical applications have had varying levels of success, with immunotherapeutic agents, such as cytokines, anti-cytokine antibodies and vaccines, proposed, tested and sometimes approved for use. These treatments options for melanoma are outlined and discussed in Chapter 51.
Nonmelanoma Skin Cancer (NMSC)
Squamous Cell Carcinoma
Cutaneous SCC is the second most common human cancer, affecting greater than 300,000 individuals in the US annually [1, 5]. While most cases are treated successfully with local removal, aggressive cases can metastasize to local lymph nodes and distant organs. These aggressive cases are responsible for the approximately 10,000 non-melanoma skin cancer deaths in the US each year [1].
SCC is a malignant proliferation of the keratinocyte that tends to occur on sun-damaged skin. It often progresses from noninvasive precursor lesions, such as actinic keratosis (AK). It presents in a variety of forms, from a crusted patch or nodule, to an ulcer, to a hyperkeratotic indurated papule.
SCC Gene Expression and Immune Cell Profile
The immune microenvironment of SCC is unique, both in the cells that are local to the tumor and their ability to be stimulated, as well as the presence of various cytokines (Fig. 42.1). The gene expression profile of SCC shows a relatively immunosuppressed microenvironment [6]. In studies of immune response gene expression in SCC as compared to normal skin and psoriasis, a number of stimulatory genes are downregulated. These genes include the gene for cytotoxic T cell product granzyme B, the activated T-cell marker CD69 and the proinflammatory mediator inducible nitric oxide synthase (iNOS), an enzyme that is key in tumor immunity [6]. Additionally, invasive SCC showed a change in cytokine gene expression, with an increase in IL-24 expression as compared to AK or SCC in situ. SCC was also found to have increased expression of protumoral factor matrix metalloprotease 7 (MMP-7), which was shown to be induced by IL-24 in culture. IL-24 is thought to contribute to SCC invasion through the upregulation of MMP7 [7].
The evidence of immunosuppression in SCC continues with the lack of particular immune cells in the local environment; NK cells, B cells and monocytes are rarely detected around SCC [8]. Each of these cells has been shown to play a role in tumor cell eradication. NK cells are lymphocytes that were first identified for their ability to kill tumor cells without deliberate immunization or activation [9]. Monocytes exhibit considerable selective cytocidal activity against tumor cells through the generation of reactive oxygen species (ROS) [10]. Though some studies have shown resting B cells to inhibit T-cell mediated regression of tumor cells, other studies have shown the key role that activated B cells play in T cell activation and creation of long term responses against cancer [11]. The collective scarcity of these cells in SCC may play a role in SCC‘s ability to establish itself, as well as grow and metastasize.
The presence of the myeloid-derived suppressor cells (MDSCs) provides further evidence and mechanisms for SCC- related immunosuppression. MDSCs are potent suppressors of T-cell mediated responses, partially due to the downregulation of E-selectin on vascular endothelial cells. The lack of E-selectin on endothelial cells restricts T-cell entry into tumors and is caused by the presence of nitric oxide (NO) in the microenvironment. SCC-infiltrating MDSCs have been shown to produce NO, thus contributing to the immune evasion of the tumor. A possible therapy of suppressing NO production through inhibiting inducible NO synthase (iNOS) has been shown to induce E-selectin expression in vitro and may be effective as a future therapy for SCC [12].
Tumor-Associated Macrophages in SCC
Macrophages are a major population of leukocytes that are found surrounding and infiltrating solid tumors [13]. In SCC, macrophages have been shown to be far more abundant than in normal skin [14]. These peritumoral and penetrating macrophages, as mentioned earlier, are defined as tumor-associated macrophages (TAMS) [15]. TAMS play a significant role in tumor behavior, with potential to inhibit or stimulate tumor growth. Some studies have shown TAMs are capable of eradicating tumor cells in vitro, yet others have correlated a poor prognosis with increased numbers of TAMS [16–18]. In their role in aiding and abetting the tumor, TAMS can fail to identify tumor antigens and can release angiogenic and tumor stimulating factors [19, 20]. It is suspected that the tumors themselves may be creating a dynamic microenvironment that transforms the TAMS into macrophages that allow for tumor growth [21].
Despite the potential ability of TAMS to inhibit tumor progression, an increased number of TAMS is correlated with a negative prognosis. This can be explained by a number of factors. In studies, TAMS have been shown to make matrix metalloproteinases (MMP)9 (gelatinase B) and 11 (stromelysin-3), zinc-dependent proteinases that participate in extra-cellular matrix degradation, which allow direct tumor invasion, as well as release pro-angiogenic factors otherwise sequestered within the extra-cellular matrix [14, 22]. This is in contrast to macrophages in normal skin, which produce these factors at lower levels than TAMS in the SCC microenvironment.
The macrophages of the SCC microenvironment have also been shown to be predominantly M2 macrophages, or alternatively activated macrophages. These macrophages are induced by IL-4, in contrast to M1 macrophages, or classically activated macrophages, which are induced by IFN-γ. A strong M1 macrophage response is thought to prevent tumor growth. In contrast, M2 macrophages have a lower antigen presenting capacity and have been positively correlated with tumor genesis and progression through inflammation. Recent studies have shown SCC- associated macrophages to be heterogeneously activated, with some expressing M1 markers, some expressing M2 markers and some expressing both M1 and M2 markers simultaneously [14]. This heterogeneous activation of TAMS in SCC gives rise to a potential therapy in driving TAM activation to the M1 anti-cancer phenotype.
TAMS have been shown to play a role in lymphangiogenesis, with the expression of vascular endothelial growth factor-C (VEGF-C) [23]. VEGF-C, a critical lymphangiogensis mediator, promotes increased lymph vessel density and has been correlated with increased risk of metastasis in squamous cell carcinomas of the oral cavity and melanoma [24, 25]. The increased lymph vessel density spurred by VEGF-C is an important factor in cancer’s development and spread.
With production of high levels of MMPs, expression of lymphangiogenic mediator VEGF-C and M2 characteristics, TAMS in SCC are failing to prevent tumor creation and progression and are rather promoting its survival and advancement. The overall behavior and subtype of TAMS in SCC show the immunosuppressive potential of immune cells when influenced by the tumor environment.
Dendritic Cells and SCC
Dendritic cells (DCs), the most potent antigen-presenting cell, exist in a variety of subtypes, and regulate the adaptive immune system [26, 27]. They are key players in cancer immune surveillance, with their ability to stimulate tumor-specific T-cell responses, along with having been shown to infiltrate various human tumors [28–31]. DCs are abundant in the skin immune system, existing mainly as epidermal Langerhans cells (LCs) and dermal myeloid DCs. LCs, with their epidermal localization, should be the first antigen presenting cell to encounter SCC tumor antigen, as SCC is a malignant proliferation of epidermal keratinocytes.
However, studies have shown that DCs from human cancers are often functionally compromised, with a decreased ability to induce IFN-γ and stimulate T-cells [32, 33]. Further studies have shown that the tumor microenvironment contains immunosuppressive cytokines which impair DC differentiation and function [26, 34].
With regards to DCs, SCC have been shown to have a relatively immunosuppressed microenvironment, with a lack of mature dendritic cells in comparison to normal skin (Fig. 42.2) [35, 36]. This is seen by the down-regulation of mature dendritic cell marker gene CD83 and decreased numbers of CD83 cells in SCC [6].
Additionally, SCC-associated mature myeloid dendritic cells (mDCs) have been shown to be functionally compromised and deficient in their ability to produce IFN-γ and stimulate T-cells, an important indication of the immunosuppressed microenvironment [37]. Even when cultured with mDC-maturing cytokines like IL1b, IL-6,TNF-α, and PGE2, SCC-associated mDCs remained impaired in their T–cell proliferation stimulation. This is despite their phenotypic maturity that is comparable to the mDCs of normal skin. This is thought to be due to the fact that the SCC cytokine milieu has been shown to be composed of immunosuppressive cytokines that suppress myeloid DCs, such as VEGF-A, TGF-β, IL-10, and IL-6 [37].
Langerhans cells (LCs) from SCC seem to be more capable of immune response than their dermal counterparts. LCs from SCC, in contrast to mDCs, have been shown to elicit a type 1 immune response when activated. Moreover, LCs from SCC have been shown to be more powerful stimulators of CD4 and CD8 T cell proliferation than those from normal skin and elicit a more powerful type 1 T-cell response. They also express higher levels of surface markers CD40, CD80, CD83, and CD86 than LCs from normal skin, making them more mature and is an important factor in immune response induction [38].
However, SCC-derived LCs still may have some limitations based on their gene profile. They show a mixed gene profile of upregulated immune activation genes, such as STAT4, IL15, and CD80 as well as upregulated immune tolerance genes, such as CD200 and receptor activator of NF-KB [38]. This mixed activation and tolerance profile is indicative of the tumor environment’s effect on the LCs and more is still to be learned about how this impacts their behavior.
Basal Cell Carcinoma
Basal cell carcinoma (BCC) is the most common human malignancy, with a higher prevalence than all other malignant tumors combined. BCC is a malignant proliferation of keratinocytes from the basal layer of the epidermis. Sun exposure is the most important risk factor for BCC, but other risk factors include age and fair skin. BCC is slow-growing and highly curable, but can be extremely disfiguring if allowed to progress without intervention. BCC has a number of clinical presentations, spanning cystic, ulcerated, nodular, superficial, sclerosing, pigmented, and keratotic variants.
Cytokine and Chemokines in BCC
In BCC, a number of cytokines and chemokines are associated with its avoidance of immunosurveillance and subsequent development. Of the proinflammatory cytokines, IL-6, IL-8, IL-17, IL-22, and CXCL12 have been linked to BCC tumor progression. IL-6 has been shown to increase anti-apoptotic activity within BCC cell lines [39] and promote angiogenesis through the PI3k/Akt pathway, as well as through increasing the expression of the pro-angiogenic cytokine IL-8 [40, 41]. CXCL12 has also been shown to promote angiogenesis by binding to the CXCR4 receptor, which is expressed to a higher degree in more aggressive forms of BCC [42]. CXCL12 also upregulates the activity of matrix metalloprotease 13 (MMP-13), allowing for BCC invasion [43].
IL-17 and 22 have also been shown to increase proliferation and migration of BCC in vitro and tumor progression in vivo, through both their intrinsic signaling pathways and the induction of IL-6 and 8 production [44]. IL-10, an immunosuppressive cytokine, is upregulated in BCC and may contribute to the immunosuppressed microenvironment of the tumor [45]. Its presence has been correlated with lack of HLA-DR, ICAM1, CD40, and CD80 expression, surface markers that aid in immune detection, as well as being correlated with immune cell maturity [46].
IFN-γ is a cytokine that has been shown to stimulate immune responses against cancer. In concordance with a permissively immunosuppressed microenvironment, BCC has decreased expression of IFN-γ receptor, which may play a part in the lack of cell-mediated immune response to BCC [47]. Conversely and logically, IFN-γ is elevated in actively regressing BCC [48]. Interestingly, IL-23, a cytokine which induces IFN-γ production as well as inducing antitumor effects in vitro, has also been shown to be elevated in BCC [49].
Fas ligand (FasL) is an apoptosis-inducing factor that by binding to its receptor on the cell surface, begins the apoptotic cascade of signaling within the cell. It is a member of the tumor necrosis factor family of receptor-ligand binding. When FasL is expressed by cancer cells, it induces the apoptosis of infiltrating lymphocytes, allowing the cancer to evade immune surveillance (Fig. 42.3). Some studies have shown BCC to express FasL, while others have had the opposite results, making the expression of FasL on the part of BCC still debatable [50–52].
In general, BCC is associated with a Th2 dominant microenvironment, which is the immune response correlated with immune tolerance. It is capable of significantly inhibiting the Th1 anti-tumor immune response. The Th2 environment is shown with increased expression of IL-4, IL-10, and CCL22, a chemokine responsible for regulatory T cell chemotaxis. However, the BCC microenvironment has also been shown to have an increased expression of interferon-associated genes and IL-23 expression, favoring a Th1 microenvironment [49]. This conflicting microenvironment, shown by the immunostimulatory and immunsuppressive cytokines in the BCC tumor milieu, is consistent with a dynamic state within the immune microenvironment.
Immune Cells and BCC
Dendritic cells, as mentioned earlier, are key in cancer immune surveillance and often have altered behavior in the unique microenvironment of the tumor. In the skin, they exist mainly as epidermal Langerhans cells (LCs) and dermal myeloid DCs. The presence and density of DCs in BCC is controversial, as studies have shown conflicting results. Some studies have shown a decrease and even absence of mature LCs, particularly in tumors of the face, and immature myeloid DCs were found to be present [49, 53], similar to the dendritic cell profile seen in SCC. This decrease in LC density in BCC is linked to increased aggressive behavior on the part of the tumor [54]. Additionally, in BCC cells, the depletion of macrophages and LCs resulted in enhanced tumor progression [55].
Other studies have shown an increased density of LCs within the BCC lesion, as well as in adjacent epithelium [56, 57]. An increase LC density within the BCC lesion is particularly associated with smaller tumor size and tumor location to the face [58]. One explanation for the contradiction in presence or absence of DCs in BCC that has been suggested is that the density of DCs in BCC changes over time, with an initial reduction allowing initiation and subsequent host response increasing DC density [59]. This is also consistent with the dynamic microenvironment suggested by the mixed cytokine profile of BCC.
Regulatory T cells (Tregs) are immune suppressive T cells, important in self-tolerance and immune homeostasis. Created in the thymus, they normally comprise 5–10 % of the CD4 T cells in the periphery. They can also be induced in the periphery from naïve T cells [60]. Both induced and natural Tregs express the transcription factor forkhead box P3 (FOXP3), an important controller of suppressor protein expression and used to identify Tregs [61]. These cells have been found to surround BCC, which is consistent with the increased expression of the chemokine CCL22 (Fig. 42.4). This surrounding of BCC by Tregs can contribute to the immune evasion of the tumor, possibly through the impaired maturation of DCs [49].
Mast cells are also thought to contribute to the immunosuppressed microenvironment of BCC. They have been shown to accumulate at the periphery of BCC, especially in aggressive BCC tumors [62, 63]. Additionally, they participate in matrix degradation through the release of proteases, which allow tumor spread and contribute to tumor angiogenesis as a source of VEGF [64, 65], similar to the TAMS of SCC.
Imiquimod
With all the cytokines and immune cells contributing to an immunosuppressed BCC microenvironment, immunomodulatory therapy options were a logical next step to explore. Imiquimod, one of the most successful therapies, is a topical treatment for BCC that has been shown to induce apoptosis in BCC [66]. It is an immune modifier and, more specifically, a Toll-like-receptor-7 (TLR-7) agonist, which induces multiple cytokines, stimulating an innate and adaptive cell-mediated immune response [67].
Imiquimod treatment results in various immune cells invading in stages. The tumor is initially infiltrated by CD4 T cells, followed by a massive intratumoral and peritumoral infiltration of macrophages, as well as activated DCs [68]. The plasmacytoid DCs are recruited by imiquimod’s stimulation of Th1 cytokines, including IL-12. Imiquimod treatment efficacy has been linked to pretreatment DC density in the tumor, with a greater efficiency being shown with a higher density of pretreatment DCs [69]. Imiquimod also induces IFN-α, which in turn induces cell surface expression of FasR on the tumor cells, causing apoptosis of the tumor cells through the CD95 receptor ligand interaction [70–72].
Immunosuppression and Transplant-Associated NMSC
As evidenced by the previous points, the immune system plays a crucial role in the development and progression of non-melanoma skin cancer (NMSC). The most important risk factor for non-melanoma skin cancers is UV radiation. In addition to their mutagen properties, UVA and UVB have been shown to be immunosuppressive in humans. Studies have shown that UVA irradiation suppresses memory immunity to the seven antigens in the delayed-type hypersensitivity test Merieux [73, 74]. Additionally, irradiation with half the UVA in minimal erythema dose (MED), the amount of sunlight necessary to cause a sunburn, suppressed recall immunity to nickel [75]. In animal studies, lymphocytes from UV irradiated mice were unable to prevent malignant formation on UV-irradiated skin grafts in unirradiated mice [76]. Transplanted tumor cell lines, including SCC, which would be immunologically rejected in immunologically competent mice, were able to grow in UV immunosuppressed mice.
Another example of immunosuppression leading to increased risk of NMSC, as well as more aggressive behavior by the NMSC, is the occurrence of these cancers in patients with HIV infection. Immunosuppressed HIV-positive patients can develop rapidly growing cutaneous SCCs at a young age, with an increased risk of recurrence and metastasis [77].
The most obvious and important evidence linking immunosuppression and NMSC is seen in immunosuppressed organ transplant recipients (OTR), with SCC incidence being 60 to 100 times greater in this population than in the age-matched immunocompetent population [78]. The OTR population also has a greater likelihood of multiple skin cancers at presentation (Fig. 42.5) [79].
Furthermore, SCC in OTR is more aggressive, with a higher probability of recurrence and metastasis [80]. The risk of SCC in OTR seems to be directly proportional to the level of immunosuppression, with lower numbers of CD4 cells found in OTRs with NMSC versus OTRs without NMSC [81, 82].
This altered incidence and behavior of SCC in immunosuppressed patients can be attributed to the altered immune microenvironment. With regards to the modified microenvironment, transplant associated SCC (TSCC) has increased populations of immune cells that are immunosuppressive and produce pro-tumoral cytokines, as well as decreased populations of immune cells that initiate a Th1 (cell–mediated immunity) antitumor immune response [83].
The immunosuppressed TSCC immune microenvironment is altered in its T-cell populations and ratios. More specifically, TSCC has been shown to have increased IL-22-producing CD8+ cytotoxic T cells compared to immune competent SCC, as well as increased expression of IL22 receptors [84]. IL-22 is a pro-inflammatory cytokine typically involved in wound healing, which causes activation of genes involved in cell cycle progression and the prevention of apoptosis [85]. IL-22 has been shown to have pro-tumoral activity in multiple cancers. IL-22 has been shown to drive SCC proliferation in culture in a dose-dependent manner, most dramatically under starvation conditions [84]. This is in concert with the idea that IL-22 may drive SCC proliferation within the tumor, where there are high metabolic demands and diminished enrichment.
Additionally, the CD8+ IFN-γ producing T cells in TSCC are decreased compared to SCC, which is associated with aggressive tumor behavior and increased metastasis [86]. TSCC also has an increased proportion of regulatory T cells (Tregs), which has been correlated with a poor prognosis in other carcinomas, such as breast and gastric (Fig. 42.6) [87, 88]. Tregs are important in preventing autoimmunity, but may suppress beneficial antitumor activity and aid in immune evasion [88–90].
TSCC has also been shown to have decreased CD4+ helper T (Th) cells infiltrating the tumor and reduced mRNA for IL17A. IL17A is a Th17-specific cytokine that is involved in inflammation and the recruitment of the innate immune system [91, 92]. The decreased IL17A favors graft tolerance but may weaken the host’s anti-tumor response against the TSCC [93–96].
The skin adjacent to TSCC in OTRs has been shown to be Th2 immune response weighted, with decreased IFN-γ levels [83]. The Th2 gene expression is correlated with transplant tolerance and long-term allograft survival [97]. However, as mentioned earlier, the Th2 response is capable of significantly inhibiting the Th1 response, which is the anti-tumor immune response. This allows for the increased aggressiveness and recurrence rates of SCC in OTRs [83].
These changes in the immune microenvironment suggest a compromised inflammatory response in the SCC of OTRs. This alters the behavior and prognosis of TSCC but is a necessary component of immunosuppression for graft tolerance. Though a minimization of immunosuppression in heart and kidney transplant recipients showed reduction in the development of new SCC at 5 years [98], this reduction is not always feasible. A change in immunosuppression regimen should be considered, with calcineurin inhibitors being linked to higher incidences of cutaneous carcinomas, and sirolimus or everolimus being a better choice with respect to cutaneous tumorigenesis [99]. Lastly, the current knowledge of the immune microenvironment of TSCC opens new avenues of study, with cytokines like IL-22 being possible targets in future TSCC prevention and treatment.
Melanoma
Melanoma incidence rates have been increasing over that last three decades, and greater than 75,000 new cases are projected to be diagnosed in 2014, with over 9500 deaths estimated to occur. Although melanoma is only 4 % of all skin cancers, it accounts for greater that 80 % of skin cancer deaths. About a quarter of melanoma patients will experience recurrence and advanced stage disease [2].
The Immunogenicity of Melanoma
Melanoma is considered an extremely immunogenic tumor, with the capability of triggering host immunologic response. The immunogenicity is seen in the immune cell infiltrates that are often seen in melanoma tumors, as well as the relatively high rate of spontaneous regression with concurrent vitiligo. Many melanoma-specific antigens have been identified in triggering a T-cell immune response. Additionally, a number of immune therapies, such as IFN-α and IL-2, have been shown to be effective in patients, as discussed in the chapter 51 [100, 101].
Despite the established immunogenicity of the tumor, there are a number of immune suppressive mechanisms demonstrated to occur in melanoma, such as impaired antigen-presenting cell maturation, T cell anergy, the induction and recruitment of Tregs, and myeloid-derived suppressor cells [100, 102]. Thus, boosting or stimulating an immune response against melanoma has been and is still a promising avenue for therapy, and its exploration has resulted in some success with regards to disease-free and overall survival [103].
BRAF
In approximately half of human melanomas, activating mutations in the protein kinase BRAF allow the tumor cells to survive and proliferate [2]. BRAF is a proto-oncogene that is part of the RAF kinase family of growth signal transduction. This has been shown to be through the MEK/ERK pathway, which is important in cell division and differentiation. The most common mutation is the V600E BRAF, where a valine at position 600 is replaced by a glutamic acid. This mutated BRAF also has been linked to a deactivated AMPK, or AMP activated protein kinase, which inhibits cell growth in low energy states [104]. With AMPK deactivated, the melanoma cells can then grow despite lack of nutrients.
T Cell Anergy
Melanoma has multiple mechanisms for inhibiting the activation, proliferation and effector status of T cells. This primarily includes stimulating receptors on T cells, including those for PD-L1 and the B7-H4, both members of the same family of co-stimulatory molecules [101].
PD1 is an immunoinhibitory receptor on T cells that plays a crucial role in melanoma’s immune escape. The PD1 ligand (PD-L1 or B7H1) is a member of the B family of costimulatory molecules that provides either an inhibitory or stimulatory secondary signal to T cells primarily binding HLA molecules on tumor cells. More specifically, the B7 family has been shown to control the effector phase of T-cell responses [105]. Specific tumors, such as prostate and renal cell carcinoma, have been shown to express B7 co-stimulatory molecules, which are involved in their escape from immunosurveillance [106].
PD-L1 has been found to be expressed by melanoma tumor cells. When the PD-L1 on the melanoma cell binds to the PD1 receptor on T cells, it causes an inhibition of T cell proliferation, survival and effector functions, such as cytotoxicity and cytokine release. It also induces apoptosis of tumor-specific T cells and promotes differentiation of CD4 T cells into regulatory T cells. Lastly, it increases the resistance of tumor cells to cytotoxic T cell attack [105]. Increased PD-L1 expression by melanoma is negatively correlated with survival (Fig. 42.7) [107].
This pathway is therefore an important therapeutic target, with anti-PD-L1 antibodies, such as nivolumab, tested as immunotherapeutic agents, either alone or in combination with other immune therapies. These have shown some success, but await further testing and demonstration of clinical effectiveness.
Another member of the B family of co-stimulatory molecules, B7-H4, has also been indicated in immune evasion of melanoma. Melanoma tumor cells have been found to express B7-H4, and its presence was shown to also have an inhibitory effect on T-cell cytokine production, in particular IFN-γ, TNF-α and IL-2 [101]. These cytokines are all integral to the T-cell mediated anti-tumor response. As mentioned above, high levels of PD-L1, or B7-H1, have been shown to correlate with reduced patient survival in melanoma. B7-H4 has also been associated with poor patient outcomes, with lower expression levels correlated with better survival [107].
Regulatory T Cells and Melanoma
Tregs, as mentioned earlier, are a dominant mechanism of tumor immune escape. Tregs are overrepresented in the peripheral blood of patients with melanoma and are found in the tumor microenvironment and affected lymph nodes as well [108]. The percent of Tregs infiltrating the melanoma lesions has been shown by some studies to negatively correlate with survival [109]. An even better predictor of survival is the ratio of CD8 T cells to Tregs in the tumor microenvironment [110].
Tregs are thought to accumulate in the melanoma tumor microenvironment through a number of mechanisms. As mentioned earlier, Tregs are both being induced by PD-L1 expressing melanomas and selectively surviving, as melanomas expressing PD-L1 are causing apoptosis in effector T cells. Secondly, chemokine secretion and integrin ligand expression of the melanoma tumor cells attracts Tregs from the periphery. Thirdly, immunosuppressive cytokines locally secreted by melanoma, such as TGF-β and IL-10, can induce and expand Treg populations [100].
Tregs’ immunosuppressive capabilities are enhanced through molecular mechanisms, such as melanoma’s expression of indoleamine 2,3 dioxygenase (IDO), IDO is an immunomodulatory enzyme which allows tumor cell immune escape through the depletion of tryptophan [111].
As Tregs are clearly an important part of melanoma’s immune microenvironment and its ability to progress despite melanoma’s immunogenicity, the removal or suppression of Tregs would seem to be a target ripe for therapeutic intervention. Despite many promising studies, clinical efficacy has not yet lived up to its potential, with agents based on IL-2 suppression (a crucial cytokine for Treg activation and proliferation) and FOXP3 vaccination not consistently showing improvement. Other emerging therapies that modulate Tregs, such as CTLA-4 blocking agents (CTLA-4 serves as an inhibitory molecule constitutively expressed by Tregs) and PD-1 blocking agents, have shown some success and need to be explored further [100].
Other Immunomodulatory Mechanisms of Melanoma
Some of the most important cells in melanoma immune modulation are myeloid-derived suppressor cells (MDSCs). As mentioned earlier, these cells are potent suppressors of T-cell mediated responses and contribute to immunosuppression in SCC. MDSCs contribute to melanoma tumor immune tolerance by releasing adenosine, an important immune regulator that is known to hamper the adaptive immune response [112, 113]. The adenosine receptor subtype A2a inhibits T-cell functions. Additionally, the A2b receptor subtype, activated by high adenosine levels in the hypoxic tumor microenvironment, has been shown to promote the expansion of MDSCs and accumulation in melanoma tissue, leading to an immune suppression cycle. MDSCs are also attracted by other inflammatory mediators produced during tumor progression [114].
Another common immune evasion mechanism is the downregulation or alteration of the HLA class I molecule necessary for antigen presentation, immune recognition, and anti-tumor response [115, 116]. A mechanism of HLA molecule expression downregulation noted in metastatic melanoma is through the loss of beta2-microglobulin (B2m), an important component of the HLA molecule. The B2m deficiency is mediated by a mutation of one copy of the B2m gene, followed by the loss of the other copy, i.e. loss of heterozygosity. The decrease in B2m and subsequent decrease in HLA class 1 molecule expression is correlated with decreased CD8 T cell tumor infiltration [117]. This loss may be an early event in tumor progression, leading to melanoma cells immune evasion of T cells and eventual metastasis [118].
Immune Therapy
Though melanoma is extremely immunogenic, in cases where it persists and even metastasizes, it employs multiple methods of immune evasion. Therefore, immune modifiers are important therapeutic avenues of exploration. IL-15 is a cytokine that stimulates innate and adaptive immunity, making it a logical therapeutic option to be explored in melanoma. It shares a receptor with IL-2, a similarly immunostimulatory cytokine, and in studies both IL-15 and IL-2 augment NK cell cytotoxic activity and increase transcription of perforin in vitro [119]. In trials, IL-15 delivered to melanoma resulted in tumor regression and increased long term survival, as well as resulting in an influx of NK and memory CD8 T cells [120, 121].
Diphencyprone (DPCP) is a topical immunotherapeutic agent that is currently in clinical trials as a therapy for melanoma. It has demonstrated melanoma regression with treatment in early studies. Melanoma’s regression with DPCP treatment is thought to be due to TH17 lymphocytes, the immune modulator subset of T helper cells, possibly through TLR4 signaling [122].
Many other immune therapies for melanoma have been and are currently being explored, including, as mentioned earlier, vaccines to certain cell markers, immunostimulatory cytokines and modulations of populations of immune cells present in melanoma’s immune microenvironment. All of this is discussed further in Chapter 51.
Responsiveness to Immune Therapy
The presence and distribution of tumor-infiltrating lymphocytes (TILs) may be prognostically useful in melanoma. Their quantity has been qualified as absent, brisk, or non-brisk with a brisk grading in some studies predicting better disease-free and overall survival outcomes, independent of sex, age, and tumor stage. This has been contradicted by other studies showing the presence of TILs promoting tumor outgrowth and metastasis [123–125].
These differences in outcome can be explained by a difference in the cohort of patients examined, and more importantly, a lack of differentiation between different phenotypes. With CD4 and CD8 T cells infiltrating, the distinctions are crucial, as CD8 T cells can be inactivated and anergic, and CD4 T cells are a heterogeneous group and can be composed of Th1, Th2 or Tregs [123].
The genetic expression profile of melanoma is also a good predictor of its responsiveness to immune therapy. Melanomas with an upregulation of immune-related genes have been shown to have a favorable clinical response. The specific immune genes upregulated are the IFN-stimulated genes, the CXCR5/CCR5 ligands, the chemokine genes and the genes associated with immune effector functions. Besides a favorable response to immune therapy, the gene expression profile of immune activation was correlated with a good prognosis in melanoma patients [126].
Conclusion
Cutaneous malignancies are among the most common human cancers and compose a very significant health burden. The interaction between the immune microenvironment and the tumor is crucial in determining the tumor’s ability to establish itself, grow and metastasize. The interplay between the tumor cells and the immune system has demonstrated the different mechanisms of immune evasion and suppression employed by both NMSCs and melanoma. These include a modulation of the cancer gene profile, such as the downregulation of stimulatory genes key in tumor immunity. Additionally, the mechanisms involve changing which populations of immune cells are present in the tumor microenvironment, such as having fewer NK cells and more Tregs present. Lastly, the cytokine profile surrounding these cancers is altered, enhancing tolerance, such as the switch to a TH2 cytokine profile. The understanding of the immune microenvironment of cutaneous malignancies is crucial, as it affords many targets for therapeutic options. There is still much more to explore and understand about the immune microenvironment of each cutaneous malignancy and as more is discovered, there are more opportunities to efficiently treat and cure these cancers.
References
Weinberg AS, Ogle CA, Shim EK. Metastatic cutaneous squamous cell carcinoma: an update. Dermatol Surg. 2007;33(8):885–99.
Shah DJ, Dronca RS. Latest advances in chemotherapeutic, targeted, and immune approaches in the treatment of metastatic melanoma. Mayo Clin Proc. 2014;89(4):504–19.
American Cancer Society. Cancer facts and figures 2016. Atlanta: American Cancer Society; 2016. http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-047079.pdf.
van Kempen LC, et al. The tumor microenvironment: a critical determinant of neoplastic evolution. Eur J Cell Biol. 2003;82(11):539–48.
Brantsch KD, et al. Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. Lancet Oncol. 2008;9(8):713–20.
Haider AS, et al. Genomic analysis defines a cancer-specific gene expression signature for human squamous cell carcinoma and distinguishes malignant hyperproliferation from benign hyperplasia. J Invest Dermatol. 2006;126(4):869–81.
Mitsui H, et al. Gene expression profiling of the leading edge of cutaneous squamous cell carcinoma: IL-24-driven MMP-7. J Invest Dermatol. 2014;134(5):1418–27.
Terao H, et al. Immunohistochemical characterization of cellular infiltrates in squamous cell carcinoma and Bowen’s disease occurring in one patient. J Dermatol. 1992;19(7):408–13.
Wu J, Lanier LL. Natural killer cells and cancer. Adv Cancer Res. 2003;90:127–56.
Mytar B, et al. Cross-talk between human monocytes and cancer cells during reactive oxygen intermediates generation: the essential role of hyaluronan. Int J Cancer. 2001;94(5):727–32.
Nelson BH. CD20+ B cells: the other tumor-infiltrating lymphocytes. J Immunol. 2010;185(9):4977–82.
Gehad AE, et al. Nitric oxide-producing myeloid-derived suppressor cells inhibit vascular E-selectin expression in human squamous cell carcinomas. J Invest Dermatol. 2012;132(11):2642–51.
Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5(12):953–64.
Pettersen JS, et al. Tumor-associated macrophages in the cutaneous SCC microenvironment are heterogeneously activated. J Invest Dermatol. 2011;131(6):1322–30.
Wang YC, et al. Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res. 2010;70(12):4840–9.
Nonomura N, et al. Infiltration of tumour-associated macrophages in prostate biopsy specimens is predictive of disease progression after hormonal therapy for prostate cancer. BJU Int. 2011;107(12):1918–22.
Romieu-Mourez R, et al. Distinct roles for IFN regulatory factor (IRF)-3 and IRF-7 in the activation of antitumor properties of human macrophages. Cancer Res. 2006;66(21):10576–85.
Steidl C, et al. Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med. 2010;362(10):875–85.
Lin EY, et al. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 2006;66(23):11238–46.
Lin EY, Pollard JW. Tumor-associated macrophages press the angiogenic switch in breast cancer. Cancer Res. 2007;67(11):5064–6.
Gocheva V, et al. IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev. 2010;24(3):241–55.
Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2(3):161–74.
Moussai D, et al. The human cutaneous squamous cell carcinoma microenvironment is characterized by increased lymphatic density and enhanced expression of macrophage-derived VEGF-C. J Invest Dermatol. 2011;131(1):229–36.
Boone B, et al. The role of VEGF-C staining in predicting regional metastasis in melanoma. Virchows Arch. 2008;453(3):257–65.
Sugiura T, et al. VEGF-C and VEGF-D expression is correlated with lymphatic vessel density and lymph node metastasis in oral squamous cell carcinoma: Implications for use as a prognostic marker. Int J Oncol. 2009;34(3):673–80.
Fricke I, Gabrilovich DI. Dendritic cells and tumor microenvironment: a dangerous liaison. Immunol Invest. 2006;35(3-4):459–83.
Steinman RM, Banchereau J. Taking dendritic cells into medicine. Nature. 2007;449(7161):419–26.
Chaput N, et al. The Janus face of dendritic cells in cancer. Oncogene. 2008;27(45):5920–31.
Gottfried E, Kreutz M, Mackensen A. Tumor-induced modulation of dendritic cell function. Cytokine Growth Factor Rev. 2008;19(1):65–77.
Talmadge JE. Pathways mediating the expansion and immunosuppressive activity of myeloid-derived suppressor cells and their relevance to cancer therapy. Clin Cancer Res. 2007;13(18 Pt 1):5243–8.
Vicari AP, Caux C, Trinchieri G. Tumour escape from immune surveillance through dendritic cell inactivation. Semin Cancer Biol. 2002;12(1):33–42.
Enk AH, et al. Dendritic cells as mediators of tumor-induced tolerance in metastatic melanoma. Int J Cancer. 1997;73(3):309–16.
Pinzon-Charry A, Maxwell T, Lopez JA. Dendritic cell dysfunction in cancer: a mechanism for immunosuppression. Immunol Cell Biol. 2005;83(5):451–61.
Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8(6):467–77.
Takahara M, et al. Stromal CD10 expression, as well as increased dermal macrophages and decreased Langerhans cells, are associated with malignant transformation of keratinocytes. J Cutan Pathol. 2009;36(6):668–74.
Galan A, Ko CJ. Langerhans cells in squamous cell carcinoma vs. pseudoepitheliomatous hyperplasia of the skin. J Cutan Pathol. 2007;34(12):950–2.
Bluth MJ, et al. Myeloid dendritic cells from human cutaneous squamous cell carcinoma are poor stimulators of T-cell proliferation. J Invest Dermatol. 2009;129(10):2451–62.
Fujita H, et al. Langerhans cells from human cutaneous squamous cell carcinoma induce strong type 1 immunity. J Invest Dermatol. 2012;132(6):1645–55.
Jee SH, et al. Overexpression of interleukin-6 in human basal cell carcinoma cell lines increases anti-apoptotic activity and tumorigenic potency. Oncogene. 2001;20(2):198–208.
Gambichler T, et al. Cytokine mRNA expression in basal cell carcinoma. Arch Dermatol Res. 2006;298(3):139–41.
Jee SH, et al. Interleukin-6 induced basic fibroblast growth factor-dependent angiogenesis in basal cell carcinoma cell line via JAK/STAT3 and PI3-kinase/Akt pathways. J Invest Dermatol. 2004;123(6):1169–75.
Chen GS, et al. CXC chemokine receptor CXCR4 expression enhances tumorigenesis and angiogenesis of basal cell carcinoma. Br J Dermatol. 2006;154(5):910–8.
Chu CY, et al. Involvement of matrix metalloproteinase-13 in stromal-cell-derived factor 1 alpha-directed invasion of human basal cell carcinoma cells. Oncogene. 2007;26(17):2491–501.
Nardinocchi L, et al. Interleukin-17 and Interleukin-22 promote tumor progression in human non-melanoma skin cancer. Eur J Immunol. 2014;45(3):922–31.
Kim J, et al. IL-10 production in cutaneous basal and squamous cell carcinomas. A mechanism for evading the local T cell immune response. J Immunol. 1995;155(4):2240–7.
Kooy AJ, et al. Interferon-gamma-induced ICAM-1 and CD40 expression, complete lack of HLA-DR and CD80 (B7.1), and inconsistent HLA-ABC expression in basal cell carcinoma: a possible role for interleukin-10? J Pathol. 1999;187(3):351–7.
Kooy AJ, et al. Expression of interferon-gamma receptors and interferon-gamma-induced up-regulation of intercellular adhesion molecule-1 in basal cell carcinoma; decreased expression of IFN-gamma R and shedding of ICAM-1 as a means to escape immune surveillance. J Pathol. 1998;184(2):169–76.
Wong DA, et al. Cytokine profiles in spontaneously regressing basal cell carcinomas. Br J Dermatol. 2000;143(1):91–8.
Kaporis HG, et al. Human basal cell carcinoma is associated with Foxp3+ T cells in a Th2 dominant microenvironment. J Invest Dermatol. 2007;127(10):2391–8.
Ji J, et al. Fas-ligand gene silencing in basal cell carcinoma tissue with small interfering RNA. Gene Ther. 2005;12(8):678–84.
Lee SH, et al. Fas ligand is expressed in normal skin and in some cutaneous malignancies. Br J Dermatol. 1998;139(2):186–91.
Filipowicz E, et al. Expression of CD95 (Fas) in sun-exposed human skin and cutaneous carcinomas. Cancer. 2002;94(3):814–9.
Rotsztejn H, Jesionek-Kupnicka D, Trznadel-Budzko E. Decreased number of Langerhans cells in basal cell carcinoma. J Eur Acad Dermatol Venereol. 2009;23(4):471–3.
Santos I, et al. Quantitative study of Langerhans cells in basal cell carcinoma with higher or lower potential of local aggressiveness. An Bras Dermatol. 2010;85(2):165–71.
Konig S, et al. Depletion of cutaneous macrophages and dendritic cells promotes growth of basal cell carcinoma in mice. PLoS One. 2014;9(4), e93555.
McArdle JP, et al. Quantitative assessment of Langerhans cells in actinic keratosis, Bowen’s disease, keratoacanthoma, squamous cell carcinoma and basal cell carcinoma. Pathology. 1986;18(2):212–6.
Murphy GF, et al. Local immune response in basal cell carcinoma: characterization by transmission electron microscopy and monoclonal anti-T6 antibody. J Am Acad Dermatol. 1983;8(4):477–85.
Rybka MO, et al. Density of dendritic cells around basal cell carcinomas is related to tumor size, anatomical site and stromal characteristics, and might be responsible for the response to topical therapy. Int J Dermatol. 2008;47(12):1240–4.
Leon A, et al. Mast cells and dendritic cells in basal cell carcinoma. Rom J Morphol Embryol. 2009;50(1):85–90.
Sakaguchi S, et al. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–87.
Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4 + CD25+ regulatory T cells. Nat Immunol. 2003;4(4):330–6.
Cohen MS, Rogers GS. The significance of mast cells in basal cell carcinoma. J Am Acad Dermatol. 1995;33(3):514–7.
Erkilic S, Erbagci Z. The significance of mast cells associated with basal cell carcinoma. J Dermatol. 2001;28(6):312–5.
Ch’ng S, et al. Mast cells and cutaneous malignancies. Mod Pathol. 2006;19(1):149–59.
Aoki M, et al. Mast cells in basal cell carcinoma express VEGF, IL-8 and RANTES. Int Arch Allergy Immunol. 2003;130(3):216–23.
Schon M, et al. Tumor-selective induction of apoptosis and the small-molecule immune response modifier imiquimod. J Natl Cancer Inst. 2003;95(15):1138–49.
De Giorgi V, et al. In vivo characterization of the inflammatory infiltrate and apoptotic status in imiquimod-treated basal cell carcinoma. Int J Dermatol. 2009;48(3):312–21.
Barnetson RS, et al. Imiquimod induced regression of clinically diagnosed superficial basal cell carcinoma is associated with early infiltration by CD4 T cells and dendritic cells. Clin Exp Dermatol. 2004;29(6):639–43.
Quatresooz P, Pierard GE. Imiquimod-responsive basal cell carcinomas and factor XIIIa-enriched dendrocytes. Clin Exp Dermatol. 2003;28 Suppl 1:27–9.
Stanley MA. Imiquimod and the imidazoquinolones: mechanism of action and therapeutic potential. Clin Exp Dermatol. 2002;27(7):571–7.
Urosevic M, et al. Mechanisms underlying imiquimod-induced regression of basal cell carcinoma in vivo. Arch Dermatol. 2003;139(10):1325–32.
Berman B, et al. Expression of Fas-receptor on basal cell carcinomas after treatment with imiquimod 5 % cream or vehicle. Br J Dermatol. 2003;149 Suppl 66:59–61.
Fourtanier A, et al. Measurement of sunscreen immune protection factors in humans: a consensus paper. J Invest Dermatol. 2005;125(3):403–9.
Moyal DD, Fourtanier AM. Broad-spectrum sunscreens provide better protection from the suppression of the elicitation phase of delayed-type hypersensitivity response in humans. J Invest Dermatol. 2001;117(5):1186–92.
Damian DL, Barnetson RS, Halliday GM. Low-dose UVA and UVB have different time courses for suppression of contact hypersensitivity to a recall antigen in humans. J Invest Dermatol. 1999;112(6):939–44.
Fisher MS, Kripke ML. Suppressor T lymphocytes control the development of primary skin cancers in ultraviolet-irradiated mice. Science. 1982;216(4550):1133–4.
Nguyen P, et al. Aggressive squamous cell carcinomas in persons infected with the human immunodeficiency virus. Arch Dermatol. 2002;138(6):758–63.
Lindelof B, et al. Incidence of skin cancer in 5356 patients following organ transplantation. Br J Dermatol. 2000;143(3):513–9.
Gordon Spratt EA, Carucci JA. Skin cancer in immunosuppressed patients. Facial Plast Surg. 2013;29(5):402–10.
Carucci JA. Cutaneous oncology in organ transplant recipients: meeting the challenge of squamous cell carcinoma. J Invest Dermatol. 2004;123(5):809–16.
Ducloux D, et al. CD4 lymphocytopenia as a risk factor for skin cancers in renal transplant recipients. Transplantation. 1998;65(9):1270–2.
Ulrich C, et al. Skin cancer in organ transplant recipients--where do we stand today? Am J Transplant. 2008;8(11):2192–8.
Kosmidis M, et al. Immunosuppression affects CD4+ mRNA expression and induces Th2 dominance in the microenvironment of cutaneous squamous cell carcinoma in organ transplant recipients. J Immunother. 2010;33(5):538–46.
Zhang S, et al. Increased Tc22 and Treg/CD8 ratio contribute to aggressive growth of transplant associated squamous cell carcinoma. PLoS One. 2013;8(5), e62154.
Pan H, et al. Hydrodynamic gene delivery of interleukin-22 protects the mouse liver from concanavalin A-, carbon tetrachloride-, and Fas ligand-induced injury via activation of STAT3. Cell Mol Immunol. 2004;1(1):43–9.
Kim ST, et al. Tumor-infiltrating lymphocytes, tumor characteristics, and recurrence in patients with early breast cancer. Am J Clin Oncol. 2013;36(3):224–31.
Bates GJ, et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol. 2006;24(34):5373–80.
Beyer M, Schultze JL. Regulatory T cells in cancer. Blood. 2006;108(3):804–11.
Beyer M, et al. In vivo peripheral expansion of naive CD4 + CD25high FoxP3+ regulatory T cells in patients with multiple myeloma. Blood. 2006;107(10):3940–9.
Rutella S, Lemoli RM. Regulatory T cells and tolerogenic dendritic cells: from basic biology to clinical applications. Immunol Lett. 2004;94(1-2):11–26.
Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007;8(4):345–50.
Wilson NJ, et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol. 2007;8(9):950–7.
Cho ML, et al. Cyclosporine A inhibits IL-15-induced IL-17 production in CD4+ T cells via down-regulation of PI3K/Akt and NF-kappaB. Immunol Lett. 2007;108(1):88–96.
Kopf H, et al. Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells. Int Immunopharmacol. 2007;7(13):1819–24.
Lowes MA, et al. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol. 2008;128(5):1207–11.
Zhang C, et al. Cyclosporin A inhibits the production of IL-17 by memory Th17 cells from healthy individuals and patients with rheumatoid arthritis. Cytokine. 2008;42(3):345–52.
Paul WE, Seder RA. Lymphocyte responses and cytokines. Cell. 1994;76(2):241–51.
Euvrard S, et al. Subsequent skin cancers in kidney and heart transplant recipients after the first squamous cell carcinoma. Transplantation. 2006;81(8):1093–100.
Leblanc Jr KG, Hughes MP, Sheehan DJ. The role of sirolimus in the prevention of cutaneous squamous cell carcinoma in organ transplant recipients. Dermatol Surg. 2011;37(6):744–9.
Jacobs JF, et al. Regulatory T cells in melanoma: the final hurdle towards effective immunotherapy? Lancet Oncol. 2012;13(1):e32–42.
Quandt D, et al. B7-h4 expression in human melanoma: its association with patients’ survival and antitumor immune response. Clin Cancer Res. 2011;17(10):3100–11.
Filipazzi P, Huber V, Rivoltini L. Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients. Cancer Immunol Immunother. 2012;61(2):255–63.
Page DB, et al. Checkpoint modulation in melanoma: an update on ipilimumab and future directions. Curr Oncol Rep. 2013;15(5):500–8.
Zheng B, et al. Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol Cell. 2009;33(2):237–47.
Wang W, et al. PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+ CD25(Hi) regulatory T cells. Int Immunol. 2009;21(9):1065–77.
Yi KH, Chen L. Fine tuning the immune response through B7-H3 and B7-H4. Immunol Rev. 2009;229(1):145–51.
Hino R, et al. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer. 2010;116(7):1757–66.
Jandus C, et al. Selective accumulation of differentiated FOXP3(+) CD4 (+) T cells in metastatic tumor lesions from melanoma patients compared to peripheral blood. Cancer Immunol Immunother. 2008;57(12):1795–805.
Knol AC, et al. Prognostic value of tumor-infiltrating Foxp3+ T-cell subpopulations in metastatic melanoma. Exp Dermatol. 2011;20(5):430–4.
Quezada SA, et al. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest. 2006;116(7):1935–45.
Brody JR, et al. Expression of indoleamine 2,3-dioxygenase in metastatic malignant melanoma recruits regulatory T cells to avoid immune detection and affects survival. Cell Cycle. 2009;8(12):1930–4.
Junger WG. Immune cell regulation by autocrine purinergic signalling. Nat Rev Immunol. 2011;11(3):201–12.
Sorrentino R, Pinto A, Morello S. The adenosinergic system in cancer: key therapeutic target. Oncoimmunology. 2013;2(1), e22448.
Iannone R, et al. Blockade of A2b adenosine receptor reduces tumor growth and immune suppression mediated by myeloid-derived suppressor cells in a mouse model of melanoma. Neoplasia. 2013;15(12):1400–9.
Garrido F, et al. Implications for immunosurveillance of altered HLA class I phenotypes in human tumours. Immunol Today. 1997;18(2):89–95.
Marincola FM, et al. Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol. 2000;74:181–273.
Boon T, et al. Human T cell responses against melanoma. Annu Rev Immunol. 2006;24:175–208.
del Campo AB, et al. Immune escape of cancer cells with beta2-microglobulin loss over the course of metastatic melanoma. Int J Cancer. 2014;134(1):102–13.
Vuletic AM, et al. In-vitro activation of natural killer cells from regional lymph nodes of melanoma patients with interleukin-2 and interleukin-15. Melanoma Res. 2015;25(1):22–34.
Conlon KC, et al. Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. J Clin Oncol. 2014;33(1):74–82.
Marrero B, Shirley S, Heller R. Delivery of interleukin-15 to B16 melanoma by electroporation leads to tumor regression and long-term survival. Technol Cancer Res Treat. 2014;13(6):551–60.
Martiniuk F, et al. TH17 is involved in the remarkable regression of metastatic malignant melanoma to topical diphencyprone. J Drugs Dermatol. 2010;9(11):1368–72.
Camisaschi C, et al. Immune cells in the melanoma microenvironment hold information for prediction of the risk of recurrence and response to treatment. Expert Rev Mol Diagn. 2014;14(6):643–6.
Clemente CG, et al. Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer. 1996;77(7):1303–10.
Thomas NE, et al. Tumor-infiltrating lymphocyte grade in primary melanomas is independently associated with melanoma-specific survival in the population-based genes, environment and melanoma study. J Clin Oncol. 2013;31(33):4252–9.
Vallacchi V, et al. Transcriptional profiling of melanoma sentinel nodes identify patients with poor outcome and reveal an association of CD30(+) T lymphocytes with progression. Cancer Res. 2014;74(1):130–40.
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Questions
Questions
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1.
What effect do each cutaneous form of dendritic cells (DCs) have on the immune microenvironment of SCC?
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A.
DC are unable to stimulate Th1 lymphocytes to produce Interferon-gamma
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B.
All DC subsets hyper-activated
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C.
Langerhans cells isolated from squamous cell carcinomas are more impaired than dermal DC from the same tumor
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D.
DC derived from tumors respond normally to maturational signals
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A.
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Correct answer: (A) DC derived from tumors are unable to activate Th1 lymphocytes, a key cell type in tumor surveillance
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2.
What statement best describes the role of Tregs in both BCC’s and melanoma’s tumor milieu?
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A.
Tregs directly stimulate tumor growth by secreting cytokines and prostaglandins
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B.
Tregs render tumor cells resistant to cell death by causing them to downregulate FAS
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C.
Tregs impair DC maturation, promoting tumor tolerance by the immune system
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D.
Tregs increase tumor cell mobility, by destroying extra cellular matrix
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A.
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Correct answer: (C) Tregs impair the maturation of DC
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3.
Which statements best describe melanoma’s immune evasion mechanisms?
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A.
Impaired antigen-presenting cell maturation
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B.
T cell anergy
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C.
Induction and recruitment of Tregs
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D.
Induction of myeloid-derived suppressor cells
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E.
All of the above
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F.
None of the above
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A.
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Correct answer: (E) All of the above mechanisms are active in melanoma immune evasion
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4.
What T-cell receptor(s) plays an important role in melanoma’s immune evasion (more than one response may be correct)?
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A.
CD28
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B.
CD40 ligand
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C.
Chemokine receptors
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D.
Adenosine receptor subtype A2a
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E.
PD-1
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F.
CTLA-4
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A.
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Correct answers: (D, E, F) Adenosine receptors, PD-1 and CTLA-4 are all inhibitory receptors that melanomas engage that promotes immune evasion from T cell responses
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Ovits, C.G., Carucci, J.A. (2017). Immune Environment of Cutaneous Malignancies. In: Gaspari, A., Tyring, S., Kaplan, D. (eds) Clinical and Basic Immunodermatology. Springer, Cham. https://doi.org/10.1007/978-3-319-29785-9_42
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