Abstract
Great success of anti-CTLA-4 and anti-PD-1 monoclonal antibodies (mAbs) has changed a landscape of cancer immunotherapy. Currently, there is no doubt about an importance of immune checkpoint molecules as one of the most promising targets in anticancer drugs. Thus, identification and characterization of novel checkpoint molecules other than CTLA-4 and PD-1 is a highly anticipated research subject. In addition, agonists of stimulatory co-signal molecules have a capability of enhancing antitumor immunity, rendering them attractive in anticancer drug development. From this perspective, this chapter introduces LAG-3, TIM-3, BTLA, 4-1BB, OX-40, and GITR, as representatives of potential targets which have been explored in cancer immunotherapy. Functions of these molecules in T cell immunity and antitumor effects in preclinical animal models as well as clinical trials, if available, are described here.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
1 Introduction
In recent years, immune checkpoint blockade has demonstrated substantial advances and a striking success as a novel strategy in cancer immunotherapy. Anti-CTLA4 antibody (Ab) and anti-PD-1 Ab represent approaches of immune checkpoint blockade, which have been approved by FDA as drugs for advanced melanoma in 2011 and 2014, respectively. In future, application of these antibodies (Abs) is anticipated to expand through combinations with other methods of immunotherapies, e.g., tumor vaccine and adoptive T cell transfer, as well as non-immunotherapies including chemotherapeutic drugs, kinase inhibitors, and irradiation. At the same time, further efforts have been made to identify novel checkpoint molecules besides CTLA-4 and PD-1, so as to regulate the functions of novel molecules for therapeutic purposes. In addition, agonistic Abs which deliver stimulatory co-signals to activate antitumor T cell responses have been also sought and tested by clinical trials as novel approaches in cancer immunotherapy. In this chapter, preclinical and clinical development of novel checkpoint molecules and stimulatory co-signal molecules is reviewed.
2 Novel Targets of Immune Checkpoint Molecules
As definition of immune checkpoint molecules, they deliver inhibitory co-signals into T cells and negatively regulate T cell responses. While they are expressed on T cells either constitutively on naïve status or inducibly in response to activation, the highest expression are often detected on nonfunctional status including exhausted T cells. Typically, checkpoint molecules possess unique intracellular motifs to deliver inhibitory signals, such as ITIM (immunoreceptor tyrosine-based inhibitory motif), which are crucial to render T cells that undergo functionally unresponsive status. Attenuation of immune checkpoint is capable of preventing and restoring the T cell unresponsiveness, providing the rationale for applying checkpoint-blocking Abs to cancer immunotherapy. According to the cells expressing ligands of checkpoint molecules, its blockade mediates the effect at two potential phases of T cell response, i.e., priming phase and effector phase. For instance, as CD80/CD86, ligands of CTLA-4, are expressed on professional APC including DC, blockade of CTLA-4 enhances T cell activation at the priming phase. On the other hand, PD-L1 (B7-H1), a ligand of PD-1, is expressed in the tumor microenvironment, e.g., tumor cells and tumor stromal cells, indicating that PD-1 blockade potentiates T cell functions at the effector phase. Collectively, immune checkpoint molecules for therapeutic targets should meet, at least in part, the following criteria: (1) capacity of delivering inhibitory signal to cause T cell unresponsiveness, (2) blockade of its functions to activate T cells by abrogating unresponsiveness, and (3) its expression on nonfunctional (e.g., exhausted) T cells and its ligand expression on APC or in the tumor microenvironment. LAG-3, TIM-3, and BTLA are among the promising and novel checkpoint molecules which meet these criteria.
2.1 LAG-3
LAG-3 (lymphocyte activation gene-3, CD223), a molecule belonging to immunoglobulin superfamily, has structural homology to CD4 [1]. LAG-3 binds MHC class II via its D1 domain at 60 nM Kd, several orders higher affinity than that of CD4 for MHC class II [2]. Intracellular domain of LAG-3 contains a unique motif (KIEELE), which is essential for LAG-3 functions in T cell regulation [3, 4]. Expression of LAG-3 is detected on activated T cells, starting from 24 h after stimulation, peaking at 48 h and then gradually decreasing by day 8.
Immune-regulatory functions of LAG-3 were first revealed by experiments using anti-LAG-3 mAb, in which human CD4+ T cell clone exhibited persistent proliferation in vitro when LAG-3 was blocked [5]. Later, inhibitory function of LAG-3 was further consolidated by the studies that T cells in LAG-3 knockout (KO) animals augment proliferation, accumulation, and effector functions in response to mitogenic stimuli or cognate antigens [6, 7]. Regarding T cell inhibitory mechanism of LAG-3, transfection of LAG-3 gene lacking intracellular signaling domain lost its effects, indicating an intrinsic inhibitory mechanism [4]. On the other hand, LAG-3 expression on regulatory T cells (Treg) and its role in T cell suppression was also reported [8]. Anti-LAG-3 mAb abrogated suppressive effects of Treg, and Treg from LAG-3 KO mice reduced the suppressive activity. Ectopic expression of LAG-3 on CD4+ T cells confers them suppressive potential toward other T cells. These findings suggested extrinsic mechanisms of LAG-3 in T cell inhibition. As a cell surface marker, LAG-3 expression is associated with T cell exhaustion caused by chronic infection [9]. Recent studies further indicated that functionally impaired T cells in cancer also express LAG-3 simultaneously with PD-1 [10, 11].
Therapeutic application regulating LAG-3 functions for cancer immunotherapy has been attempted by means of LAG-3-Ig fusion proteins and anti-LAG-3 mAb. Administration of LAG-3-Ig induced growth retardation and regression of various types of tumor in mouse models [12]. It has been reported that mechanisms of antitumor effects by LAG-3-Ig are dependent on its binding to MHC class II and consequent maturation and activation of APC, including upregulated expression of co-stimulatory ligands and IL-12 production [13]. A potential role of LAG-3-Ig to block LAG-3 inhibitory signal in T cell activation remains largely unexplored. In clinical studies, LAG-3-Ig has been developed as IMP321 by Immutep and tested in renal cell carcinoma by a single agent and in breast cancer in combination with chemotherapy [14, 15]. Besides LAG-3-Ig, antagonistic anti-LAG-3 mAb has been shown to restore T cell exhaustion in mouse tumor model [11]. Accordingly, phase I clinical trial of anti-LAG-3 mAb (BMS-986016 developed by Bristol-Myers Squibb) with or without anti-PD-1 mAb in solid tumor as well as hematological malignancies has been initiated. Results of the clinical studies of LAG-3-Ig and anti-LAG-3 mAb are currently awaited with great expectations.
2.2 TIM-3
TIM-3 belongs to TIM (T cell immunoglobulin) family molecules, type I membrane protein, which structurally consists of N-terminal IgV domain followed by a mucin domain, a transmembrane domain, and an intracellular domain [16]. In T cells, TIM-3 is uniquely expressed on those differentiated into IFN-γ-producing cells, such as Th1-type CD4+ and Tc1-type CD8+ T cells. Galectin-9, a soluble molecule that is upregulated by IFN-γ, was identified as a ligand of TIM-3 [17]. Binding of galectin-9 with TIM-3 triggers T cell death by dissociating Bat3 (HLA-B-associated transcript 3) from intracellular domain of TIM-3 [18]. Thus, TIM-3 plays an essential role in termination of IFN-γ-mediated inflammatory T cell responses. Consistent with this notion, blockade of TIM-3 by anti-TIM-3 or TIM-3-Ig fusion protein augments T cell responses, leading to exacerbation of autoimmune diseases and abrogation of T cell tolerance in animal models [19, 20]. Mice deficient of TIM-3 gene also demonstrated similar phenotypes [20].
In cancer immunotherapy, TIM-3 is a potential target as an immune checkpoint molecule to interfere with. TIM-3 expression is detected on tumor-infiltrating lymphocytes (TIL) in various types of cancer and associated with T cell exhaustion [21]. It should be noted that T cells expressing both PD-1 and TIM-3 represent the most deeply exhausted phenotype, in terms of proliferation and cytokine production of IL-2, TNF-α, and IFN-γ. Based on this finding, combined blockade of TIM-3 and PD-1 was tested and revealed a striking effect in tumor growth inhibition, more potent than a single blockade of either molecule [21, 22]. Restoration of T cell effector functions by dual blockade of TIM-3 and PD-1 has been reported in animal tumor models as well as T cells from melanoma patients [21, 23]. Besides direct effects on antitumor T cells, TIM-3 has been reported to promote granulocytic MDSC (myeloid-derived suppressor cells) via cognate interaction with galectin-9, which is expressed on CD11b+ Ly6G+ cells [24]. As MDSC expand in tumor-bearing hosts and facilitate immune suppression at tumor microenvironment, TIM-3 blockade could indirectly stimulate antitumor immunity by attenuating MDSC functions. In addition, recent intriguing studies discovered an increased expression of TIM-3 on leukemic cancer stem cells in patients with acute myeloid leukemia, suggesting a potential use of TIM-3 as a target for tumor killing [25, 26]. Collectively, TIM-3 could serve as a multifunctional molecule in tumor growth and antitumor immunity. Clinical trials to examine TIM-3-targeting reagents such as anti-TIM-3 mAb have yet to be initiated in cancer patients, and such studies are eagerly awaited.
2.3 BTLA
BTLA (B and T lymphocyte attenuator, CD272) was cloned from activated T cells as a molecule structurally homologous to immunoglobulin superfamily [27]. Similar to PD-1 and CTLA-4, BTLA has one IgV domain in extracellular domain, followed by transmembrane domain and intracellular domain, where two ITIM motifs exist. The ligand of BTLA is HVEM (herpesvirus entry mediator, CD270), which belongs to TNF (tumor necrosis factor) receptor superfamily [28]. By interacting with HVEM, BTLA delivers inhibitory signal into activated T cells by recruiting SHP-1/2 via its intracellular ITIM motifs [28, 29]. Consistent with these findings, mice deficient of BTLA gene exhibited exacerbated autoimmune and inflammatory diseases [27, 30] and enhanced memory T cell responses [31]. While an increased expression of BTLA on anergic T cells was reported [32], another study indicated no correlation between BTLA expression level and a severity of T cell exhaustion [33].
Based on the findings described above, a role of HVEM-BTLA interaction in tumor immunity and its potential as a therapeutic target have been explored. In animal model, blockade of BTLA signal facilitated the effects of antitumor vaccine and inhibited tumor growth in vivo [34]. In melanoma patients, HVEM expression was detected on tumor cells, and tumor Ag-specific T cells persistently express high levels of BTLA [35]. CD8+ T cells expressing BTLA were partially dysfunctional, and blockade of BTLA restored T cell proliferation and cytokine production in response to tumor Ag in vitro [33]. Thus, anti-BTLA mAb can be a novel approach of immune checkpoint blockade, although no clinical trial has initiated yet. It should be noted that HVEM-BTLA interaction can deliver bidirectional signal to both sides, where HVEM transmits stimulatory co-signal to T cells [36]. Thus, HVEM-BTLA pathway should be carefully manipulated for cancer immunotherapy, as simple blockade could diminish HVEM-mediated positive effects as well as BTLA negative signal.
3 Novel Targets of Immune Stimulatory Co-signal Molecules
Quality and quantity of T cell responses are determined by a fine balance between stimulatory and inhibitory co-signals. When stimulatory co-signals surmount inhibitory co-signals, T cells activate and generate productive responses. On the other hand, when inhibitory co-signals are dominant, T cells undergo dysfunctional state, such as anergy and exhaustion, leading to a termination of immune responses. Thus, in order to accelerate antitumor immunity, triggering stimulatory co-signals, in addition to blockade of inhibitory co-signals (=immune checkpoints), would be an important strategy. Accordingly, agonistic Abs against stimulatory co-signal molecules have been developed, and some of them are currently under clinical investigation. Abs against 4-1BB, OX-40, and GITR are among the most promising and advanced reagents in this strategy.
3.1 4-1BB
4-1BB (CD137), a molecule of TNF receptor superfamily, is inducibly expressed on T cells along with their activation. Interaction with its ligand, 4-1BBL, triggers 4-1BB stimulatory co-signal, which activates NF-κB and MAPK via recruitment of TRAF [37]. 4-1BB signal enhances T cell activation and cytokine production and promotes their survival by inducing antiapoptotic molecules such as Bcl-XL, especially in CD8+ T cells [38]. While mice deficient of 4-1BB gene exhibited a reduced number of memory CD8+ T cells in bone marrow, there is an accumulation of effector memory T cells in 4-1BB-overexpressing transgenic mice [39, 40]. Expression of 4-1BB is also detected on NK cells and DC, and stimulatory effects of 4-1BB on these cells have been also reported [41, 42].
In mouse tumor models, triggering 4-1BB stimulatory co-signal by agonistic Ab or gene transfection induced prominent effects of tumor regression [43, 44]. Mechanistically, these effects are dependent on activation of CD8+ T cells and NK cells and associated with an increased accumulation of TIL by IFN-γ secretion [45]. Based on these studies, fully human anti-4-1BB mAbs with agonistic capacity have been developed by at least two pharmaceutical companies. Although early results from clinical trials indicated a substantial liver toxicity, more detailed examinations of anti-4-1BB mAbs as monotherapy or in combination with other mAbs are currently performed in patients with solid tumors and hematological malignancies [46].
3.2 OX-40
OX-40 (CD134) is a member of TNF receptor superfamily and originally identified as an activation marker on rat CD4+ T cells [47]. Subsequent studies revealed that OX-40 is expressed on both CD4+ and CD8+ T cells upon activation, as well as NK cells, and OX-40 signal promotes proliferation, cytokine production, migration, and effector functions of these cells [48]. Mice deficient of OX-40 or OX-40L, a ligand of OX-40, exhibited impaired T cell responses in vivo, indicating a role of this pathway in providing a stimulatory co-signal to T cells [49, 50]. In animal experiments, administration of OX-40 agonists, including anti-OX-40 mAb and OX-40L-Ig fusion protein, prolonged the mouse survival in various tumor models [51]. In addition to direct effects in stimulating T cell activation, there is also evidence that OX-40 agonists dampen suppressive function of Treg, thus indirectly facilitate antitumor immunity [52, 53]. In cancer patients, the existence of OX-40-positive T cells in TIL and tumor-draining lymph nodes has been reported [54]. Phase I clinical trial using anti-OX-40 mAb demonstrated that the drug was tolerated, promoted T cell proliferation, and induced tumor shrinkage in some patients [55]. Further studies of OX-40 agonists are currently underway in clinical trials to evaluate its antitumor effects as monotherapy or in combination with other drugs.
3.3 GITR
GITR (glucocorticoid-induced TNF receptor, CD357) is expressed on various immune cells including activated T cells. GITR signal delivers stimulatory co-signal into T cells and enhances their proliferation, cytokine production, and survival [56]. Compared to other stimulatory co-signal molecules, GITR has a unique feature that is constitutively expressed on Treg at high levels, and triggering GITR signal in Treg abrogates their suppressive function [57, 58]. As expected from these findings, treatment with anti-GITR agonistic mAb caused regression of tumor in animal models [59, 60]. Further studies suggested that GITR agonists decrease the number and suppressive function of Treg at the tumor microenvironment by causing Treg instability and depletion [61, 62]. A phase I clinical trial using humanized anti-GITR agonistic mAb in advanced melanoma and other solid tumors is currently ongoing.
4 Summary
Recent development of anti-CTLA-4 and anti-PD-1 mAbs represents magnificent success in cancer immunotherapy. Accordingly, approaches to manipulate inhibitory or stimulatory co-signal functions are considered to be a rising star in the field, and identification of novel targets with a potent therapeutic potential is eagerly anticipated. While this review focuses on several novel molecules which are among the most promising and progressive in clinical translation, there are many other intriguing targets which are not introduced here. Development of novel reagents to regulate these molecules as monotherapy or combined immunotherapy with current medical interventions including kinase inhibitors, chemotherapy, and radiotherapy will establish next generation of cancer treatment.
References
Baixeras E, Huard B, Miossec C, Jitsukawa S, Martin M, Hercend T, Auffray C, Triebel F, Piatier-Tonneau D (1992) Characterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens. J Exp Med 176:327–337
Huard B, Prigent P, Tournier M, Bruniquel D, Triebel F (1995) CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins. Eur J Immunol 25:2718–2721
Workman CJ, Vignali DA (2003) The CD4-related molecule, LAG-3 (CD223), regulates the expansion of activated T cells. Eur J Immunol 33:970–979
Workman CJ, Dugger KJ, Vignali DA (2002) Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3. J Immunol 169:5392–5395
Huard B, Tournier M, Hercend T, Triebel F, Faure F (1994) Lymphocyte-activation gene 3/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T lymphocytes. Eur J Immunol 24:3216–3221
Workman CJ, Cauley LS, Kim IJ, Blackman MA, Woodland DL, Vignali DA (2004) Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J Immunol 172:5450–5455
Grosso JF, Kelleher CC, Harris TJ, Maris CH, Hipkiss EL, De Marzo A, Anders R, Netto G, Getnet D, Bruno TC et al (2007) LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest 117:3383–3392
Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, Hipkiss EL, Ravi S, Kowalski J, Levitsky HI et al (2004) Role of LAG-3 in regulatory T cells. Immunity 21:503–513
Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, Betts MR, Freeman GJ, Vignali DA, Wherry EJ (2009) Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 10:29–37
Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, Eppolito C, Qian F, Lele S, Shrikant P et al (2010) Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A 107:7875–7880
Goding SR, Wilson KA, Xie Y, Harris KM, Baxi A, Akpinarli A, Fulton A, Tamada K, Strome SE, Antony PA (2013) Restoring immune function of tumor-specific CD4+ T cells during recurrence of melanoma. J Immunol 190:4899–4909
Prigent P, El Mir S, Dreano M, Triebel F (1999) Lymphocyte activation gene-3 induces tumor regression and antitumor immune responses. Eur J Immunol 29:3867–3876
Andreae S, Piras F, Burdin N, Triebel F (2002) Maturation and activation of dendritic cells induced by lymphocyte activation gene-3 (CD223). J Immunol 168:3874–3880
Brignone C, Escudier B, Grygar C, Marcu M, Triebel F (2009) A phase I pharmacokinetic and biological correlative study of IMP321, a novel MHC class II agonist, in patients with advanced renal cell carcinoma. Clin Cancer Res 15:6225–6231
Brignone C, Gutierrez M, Mefti F, Brain E, Jarcau R, Cvitkovic F, Bousetta N, Medioni J, Gligorov J, Grygar C et al (2010) First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity. J Transl Med 8:71
Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA et al (2002) Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415:536–541
Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK (2005) The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol 6:1245–1252
Rangachari M, Zhu C, Sakuishi K, Xiao S, Karman J, Chen A, Angin M, Wakeham A, Greenfield EA, Sobel RA et al (2012) Bat3 promotes T cell responses and autoimmunity by repressing Tim-3-mediated cell death and exhaustion. Nat Med 18:1394–1400
Sanchez-Fueyo A, Tian J, Picarella D, Domenig C, Zheng XX, Sabatos CA, Manlongat N, Bender O, Kamradt T, Kuchroo VK et al (2003) Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nat Immunol 4:1093–1101
Sabatos CA, Chakravarti S, Cha E, Schubart A, Sanchez-Fueyo A, Zheng XX, Coyle AJ, Strom TB, Freeman GJ, Kuchroo VK (2003) Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat Immunol 4:1102–1110
Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC (2010) Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med 207:2187–2194
Zhou Q, Munger ME, Veenstra RG, Weigel BJ, Hirashima M, Munn DH, Murphy WJ, Azuma M, Anderson AC, Kuchroo VK et al (2011) Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood 117:4501–4510
Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, Kirkwood JM, Kuchroo V, Zarour HM (2010) Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med 207:2175–2186
Dardalhon V, Anderson AC, Karman J, Apetoh L, Chandwaskar R, Lee DH, Cornejo M, Nishi N, Yamauchi A, Quintana FJ et al (2010) Tim-3/galectin-9 pathway: regulation of Th1 immunity through promotion of CD11b+Ly-6G+ myeloid cells. J Immunol 185:1383–1392
Jan M, Chao MP, Cha AC, Alizadeh AA, Gentles AJ, Weissman IL, Majeti R (2011) Prospective separation of normal and leukemic stem cells based on differential expression of TIM3, a human acute myeloid leukemia stem cell marker. Proc Natl Acad Sci U S A 108:5009–5014
Kikushige Y, Shima T, Takayanagi S, Urata S, Miyamoto T, Iwasaki H, Takenaka K, Teshima T, Tanaka T, Inagaki Y et al (2010) TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells. Cell Stem Cell 7:708–717
Watanabe N, Gavrieli M, Sedy JR, Yang J, Fallarino F, Loftin SK, Hurchla MA, Zimmerman N, Sim J, Zang X et al (2003) BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nat Immunol 4:670–679
Sedy JR, Gavrieli M, Potter KG, Hurchla MA, Lindsley RC, Hildner K, Scheu S, Pfeffer K, Ware CF, Murphy TL et al (2005) B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat Immunol 6:90–98
Gavrieli M, Watanabe N, Loftin SK, Murphy TL, Murphy KM (2003) Characterization of phosphotyrosine binding motifs in the cytoplasmic domain of B and T lymphocyte attenuator required for association with protein tyrosine phosphatases SHP-1 and SHP-2. Biochem Biophys Res Commun 312:1236–1243
Miller ML, Sun Y, Fu YX (2009) Cutting edge: B and T lymphocyte attenuator signaling on NKT cells inhibits cytokine release and tissue injury in early immune responses. J Immunol 183:32–36
Krieg C, Boyman O, Fu YX, Kaye J (2007) B and T lymphocyte attenuator regulates CD8+ T cell-intrinsic homeostasis and memory cell generation. Nat Immunol 8:162–171
Hurchla MA, Sedy JR, Gavrieli M, Drake CG, Murphy TL, Murphy KM (2005) B and T lymphocyte attenuator exhibits structural and expression polymorphisms and is highly Induced in anergic CD4+ T cells. J Immunol 174:3377–3385
Fourcade J, Sun Z, Pagliano O, Guillaume P, Luescher IF, Sander C, Kirkwood JM, Olive D, Kuchroo V, Zarour HM (2012) CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1. Cancer Res 72:887–896
Han L, Wang W, Fang Y, Feng Z, Liao S, Li W, Li Y, Li C, Maitituoheti M, Dong H et al (2009) Soluble B and T lymphocyte attenuator possesses antitumor effects and facilitates heat shock protein 70 vaccine-triggered antitumor immunity against a murine TC-1 cervical cancer model in vivo. J Immunol 183:7842–7850
Derre L, Rivals JP, Jandus C, Pastor S, Rimoldi D, Romero P, Michielin O, Olive D, Speiser DE (2010) BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination. J Clin Invest 120:157–167
Sakoda Y, Park JJ, Zhao Y, Kuramasu A, Geng D, Liu Y, Davila E, Tamada K (2011) Dichotomous regulation of GVHD through bidirectional functions of the BTLA-HVEM pathway. Blood 117:2506–2514
Wang C, Lin GH, McPherson AJ, Watts TH (2009) Immune regulation by 4-1BB and 4-1BBL: complexities and challenges. Immunol Rev 229:192–215
Lee HW, Park SJ, Choi BK, Kim HH, Nam KO, Kwon BS (2002) 4-1BB promotes the survival of CD8+ T lymphocytes by increasing expression of Bcl-xL and Bfl-1. J Immunol 169:4882–4888
Zhu Y, Zhu G, Luo L, Flies AS, Chen L (2007) CD137 stimulation delivers an antigen-independent growth signal for T lymphocytes with memory phenotype. Blood 109:4882–4889
Pulle G, Vidric M, Watts TH (2006) IL-15-dependent induction of 4-1BB promotes antigen-independent CD8 memory T cell survival. J Immunol 176:2739–2748
Wilcox RA, Tamada K, Strome SE, Chen L (2002) Signaling through NK cell-associated CD137 promotes both helper function for CD8+ cytolytic T cells and responsiveness to IL-2 but not cytolytic activity. J Immunol 169:4230–4236
Wilcox RA, Chapoval AI, Gorski KS, Otsuji M, Shin T, Flies DB, Tamada K, Mittler RS, Tsuchiya H, Pardoll DM et al (2002) Cutting edge: expression of functional CD137 receptor by dendritic cells. J Immunol 168:4262–4267
Melero I, Shuford WW, Newby SA, Aruffo A, Ledbetter JA, Hellstrom KE, Mittler RS, Chen L (1997) Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat Med 3:682–685
Ye Z, Hellstrom I, Hayden-Ledbetter M, Dahlin A, Ledbetter JA, Hellstrom KE (2002) Gene therapy for cancer using single-chain Fv fragments specific for 4-1BB. Nat Med 8:343–348
Wilcox RA, Flies DB, Wang H, Tamada K, Johnson AJ, Pease LR, Rodriguez M, Guo Y, Chen L (2002) Impaired infiltration of tumor-specific cytolytic T cells in the absence of interferon-gamma despite their normal maturation in lymphoid organs during CD137 monoclonal antibody therapy. Cancer Res 62:4413–4418
Croft M, Benedict CA, Ware CF (2013) Clinical targeting of the TNF and TNFR superfamilies. Nat Rev Drug Discov 12:147–168
Mallett S, Fossum S, Barclay AN (1990) Characterization of the MRC OX40 antigen of activated CD4 positive T lymphocytes – a molecule related to nerve growth factor receptor. EMBO J 9:1063–1068
Gramaglia I, Weinberg AD, Lemon M, Croft M (1998) Ox-40 ligand: a potent costimulatory molecule for sustaining primary CD4 T cell responses. J Immunol 161:6510–6517
Kopf M, Ruedl C, Schmitz N, Gallimore A, Lefrang K, Ecabert B, Odermatt B, Bachmann MF (1999) OX40-deficient mice are defective in Th cell proliferation but are competent in generating B cell and CTL Responses after virus infection. Immunity 11:699–708
Chen AI, McAdam AJ, Buhlmann JE, Scott S, Lupher ML Jr, Greenfield EA, Baum PR, Fanslow WC, Calderhead DM, Freeman GJ et al (1999) Ox40-ligand has a critical costimulatory role in dendritic cell: T cell interactions. Immunity 11:689–698
Weinberg AD, Rivera MM, Prell R, Morris A, Ramstad T, Vetto JT, Urba WJ, Alvord G, Bunce C, Shields J (2000) Engagement of the OX-40 receptor in vivo enhances antitumor immunity. J Immunol 164:2160–2169
Vu MD, Xiao X, Gao W, Degauque N, Chen M, Kroemer A, Killeen N, Ishii N, Li XC (2007) OX40 costimulation turns off Foxp3+ Tregs. Blood 110:2501–2510
Piconese S, Valzasina B, Colombo MP (2008) OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection. J Exp Med 205:825–839
Vetto JT, Lum S, Morris A, Sicotte M, Davis J, Lemon M, Weinberg A (1997) Presence of the T-cell activation marker OX-40 on tumor infiltrating lymphocytes and draining lymph node cells from patients with melanoma and head and neck cancers. Am J Surg 174:258–265
Curti BD, Kovacsovics-Bankowski M, Morris N, Walker E, Chisholm L, Floyd K, Walker J, Gonzalez I, Meeuwsen T, Fox BA et al (2013) OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res 73:7189–7198
Tone M, Tone Y, Adams E, Yates SF, Frewin MR, Cobbold SP, Waldmann H (2003) Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells. Proc Natl Acad Sci U S A 100:15059–15064
Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S (2002) Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 3:135–142
McHugh RS, Whitters MJ, Piccirillo CA, Young DA, Shevach EM, Collins M, Byrne MC (2002) CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16:311–323
Cohen AD, Schaer DA, Liu C, Li Y, Hirschhorn-Cymmerman D, Kim SC, Diab A, Rizzuto G, Duan F, Perales MA et al (2010) Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLoS One 5:e10436
Turk MJ, Guevara-Patino JA, Rizzuto GA, Engelhorn ME, Sakaguchi S, Houghton AN (2004) Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J Exp Med 200:771–782
Schaer DA, Budhu S, Liu C, Bryson C, Malandro N, Cohen A, Zhong H, Yang X, Houghton AN, Merghoub T et al (2013) GITR pathway activation abrogates tumor immune suppression through loss of regulatory T cell lineage stability. Cancer Immunol Res 1:320–331
Bulliard Y, Jolicoeur R, Windman M, Rue SM, Ettenberg S, Knee DA, Wilson NS, Dranoff G, Brogdon JL (2013) Activating Fc gamma receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J Exp Med 210:1685–1693
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer Japan
About this chapter
Cite this chapter
Tamada, K. (2016). Novel Targets of Immune Inhibitory and Stimulatory Co-signals. In: Yamaguchi, Y. (eds) Immunotherapy of Cancer. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55031-0_20
Download citation
DOI: https://doi.org/10.1007/978-4-431-55031-0_20
Published:
Publisher Name: Springer, Tokyo
Print ISBN: 978-4-431-55030-3
Online ISBN: 978-4-431-55031-0
eBook Packages: MedicineMedicine (R0)