Key Points
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Cancer risk increases in transplant recipients, accounting for 10–30% of deaths in this patient population; younger recipients have the greatest increase in cancer risk, and the aggressiveness of cancers is also increased in transplant recipients
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A pro-tumorigenic environment exists in transplant recipients because immunosuppressive drugs that prevent allograft rejection also prevent immune recognition of tumour cells and promote potentially carcinogenic viral infections
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Reliable and practical strategies that induce donor-specific immunological tolerance to a transplanted organ would likely normalize the incidence of post-transplantation malignancies; however, success with these strategies thus far remains elusive
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mTOR inhibitors have immunosuppressive and anti-cancer effects that reduce the incidence and prevent recurrence of some post-transplantation tumours, but only partial inhibition occurs and the adverse effects must be counterbalanced
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Reduced need for immunosuppression, owing to improved development of new (tolerogenic) therapeutic strategies provides the best future hope for combating this increased risk of post-transplantation malignancy
Abstract
From the early days of transplantation onwards, increased cancer development in transplant recipients, who require immunosuppression to avoid graft rejection, has been recognized. Registry data indicate that approximately 10–30% of deaths are attributed to post-transplant malignancy, with an upward trend in this incidence as more patients have been exposed to chronic lifelong immunosuppression. In this Review, the overall incidence and most frequent types of cancer encountered are summarized, along with information about which transplant recipients are at the greatest risk of malignancy. Reasons for why differences exist in susceptibility to cancer in this patient population are examined, and approaches that might improve our understanding of the options available for reducing the incidence of this adverse effect of immunosuppression are described. Whether anti-rejection drugs have been successful in diminishing overall immunosuppressive burden, and consequently show any promise for decreasing post-transplant malignancies is also discussed. The topic shifts to one class of conventional anti-rejection drugs, the mammalian target of rapamycin (mTOR) inhibitors, which paradoxically have both immunosuppressive and anti-neoplastic properties. The complex activities of mTOR are reviewed in order to provide context for how these seemingly opposing effects are possible, and the latest clinical data on use of mTOR inhibitors in the clinic are discussed. The current and future perspectives on how best to normalize these unacceptably high rates of post-transplantation malignancies are highlighted.
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References
Schneck, S. A. & Penn, I. De-novo brain tumours in renal-transplant recipients. Lancet 1, 983–986 (1971).
Penn, I., Hammond, W., Brettschneider, L. & Starzl, T. E. Malignant lymphomas in transplantation patients. Transplant. Proc. 1, 106–112 (1969).
Penn, I. Occurrence of cancers in immunosuppressed organ transplant recipients. Clin. Transplant. 1998, 147–158 (1998).
Chapman, J. R., Webster, A. C. & Wong, G. Cancer in the transplant recipient. Cold Spring Harb. Perspect. Med. 3, 3:a015677 (2013).
Chapman, J. R. & Webster, A. C. Cancer after renal transplantation: the next challenge. Am. J. Transplant. 4, 841–842 (2004).
Buell, J. F., Gross, T. G. & Woodle, E. S. Malignancy after transplantation. Transplantation 80, S254–S264 (2005).
Miao, Y. et al. De novo cancers arising in organ transplant recipients are associated with adverse outcomes compared with the general population. Transplantation 87, 1347–1359 (2009).
Webster, A. C., Wong, G. & McDonald, S. Chapter 10: Cancer report. ANZA data registry [online], (2008).
van de Wetering, J., Roodnat, J. I., Haemke, A. C., Hoitsma, A. J. & Weimar, W. Patient survival after the diagnosis of cancer in renal transplant recipients: a nested case-control study. Transplantation 90, 1542–1546 (2010).
Penn, I. Occurrence of cancer in immune deficiencies. Cancer 34, 858–866 (1974).
Beyaert, R. et al. Cancer risk in immune-mediated inflammatory diseases (IMID). Mol. Cancer 12, 98–109 (2013).
Grulich, A. E., van Leeuwen, M. T., Falster, M. O. & Vajdic, C. M. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 370, 59–67 (2007).
Cobucci, R. N. et al. Assessing the impact of HAART on the incidence of defining and non-defining AIDS cancers among patients with HIV/AIDS: a systematic review. J. Infect. Public Health 8, 1–10 (2015).
Lebbé, C., Legendre, C. & Francès, C. Kaposi sarcoma in transplantation. Transplant. Rev. 22, 252–261 (2008).
Madeleine, M. M., Finch, J. L., Lynch, C. F., Goodman, M. T. & Engels, E. A. HPV-related cancers after solid organ transplantation in the United States. Am. J. Transplant. 13, 3202–3209 (2013).
Hortobagyi, G. N. Treatment of breast cancer. N. Engl. J. Med. 339, 974–984 (1998).
Hall, E. C., Pfeiffer, R. M., Segev, D. L. & Engels, E. A. Cumulative incidence of cancer after solid organ transplantation. Cancer 119, 2300–2308 (2013).
Penn, I. Cancers complicating organ transplantation. N. Engl. J. Med. 323, 1767–1769 (1990).
Kleinclauss, F. et al. Prostate cancer in renal transplant recipients. Nephrol. Dial. Transplant. 23, 2374–2380 (2008).
Brewer, J. D. et al. Malignant melanoma in solid transplant recipients: collection of database cases and comparison with surveillance, epidemiology, and end results data for outcome analysis. Arch. Dermatol. 147, 790–796 (2011).
Wisgerhof, H. C., Wolterbeek, R., de Fijter, J. W., Willemze, R. & Bouwes Bavinck, J. N. Kidney transplant recipients with cutaneous squamous cell carcinoma have an increased risk of internal malignancy. J. Invest. Dermatol. 132, 2176–2183 (2012).
Webster, A. C., Craig, J. C., Simpson, J. M., Jones, M. P. & Chapman, J. R. Identifying high risk groups and quantifying absolute risk of cancer after kidney transplantation: a cohort study of 15183 recipients. Am. J. Transplant. 7, 2140–2151 (2007).
Kiberd, B. A., Keough-Ryan, T. & Clase, C. M. Screening for prostate, breast and colorectal cancer in renal transplant recipients. Am. J. Transplant. 3, 619–625 (2003).
Walter, L. C. & Covinsky, K. E. Cancer screening in elderly patients: a framework for individualized decision making. JAMA 285, 2750–2756 (2001).
Stockfleth, E. & Claas, U. (eds) Skin cancer after organ transplantation (Springer, 2009).
Zur Hausen, H. Infections causing human cancer (Wiley-VCH Verlag GmbH & Co. KGaA, 2006).
Euvrard, S., Kanitakis, J. & Claudy, A. Skin cancers after organ transplantation. N. Engl. J. Med. 348, 1681–1691 (2003).
Ulrich, C., Kanitakis, J., Stockfleth, E. & Euvrard, S. Skin cancer in organ transplant recipients—where do we stand today? Am. J. Transplant. 8, 2192–2198 (2008).
de Gruijl, F. R. & Voskamp, P. in Skin cancer after organ transplantation (eds Stockfleth, E. & Claas, U.) 101–108 (Springer, 2009).
Bock, A., Bliss, R. L., Matas, A. & Little, J. A. Human leucocyte antigen type as a risk factor for nonmelanomatous skin cancer in patients after renal transplantation. Transplantation 78, 775–778 (2004).
Czarnecki, D. et al. Skin cancers and HLA frequencies in renal transplant recipients. Dermatology 185, 9–11 (1992).
Bouwes Bavinck, J. N. et al. Relation between HLA antigens and skin cancer in renal transplant recipients in Queensland, Australia. J. Invest. Dermatol. 108, 708–711 (1997).
Bouwes Bavinck, J. N. et al. On a possible protective effect of HLA A11 against skin cancer and keratotic skin lesions in renal transplant recipients. J. Invest. Dermatol. 97, 269–272 (1991).
Schlienger, J. L., Luca, F., Vinzio, S. & Pradignac, A. Obésité et cancer [French]. Rev. Med. Interne 30, 776–782 (2009).
Calle, E. E., Rodriguez, C., Walker-Thurmond, K. & Thun, M. J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U. S. adults. N. Engl. J. Med. 348, 1625–1638 (2003).
Agraharkar, M. L., Cinclair, R. D., Kuo, Y. F., Daller, J. A. & Shahinian, V. B. Risk of malignancy with long-term immunosuppression in renal transplant recipients. Kidney Int. 66, 383–389 (2004).
Knoll, G. et al. Canadian Society of Transplantation consensus guidelines on eligibility for kidney transplantation. CMAJ 173, 1181–1184 (2005).
Batabyal, P., Chapman, J. R., Wong, G., Craig, J. C. & Tong, A. Clinical practice guidelines on wait-listing for kidney transplantation: consistent and equitable? Transplantation 94, 703–713 (2012).
Kauffman, H. M., Cherikh, W. S., McBride, M. A., Cheng, Y. & Hanto, D. W. Deceased donors with a past history of malignancy: an organ procurement and transplantation network/united network for organ sharing update. Transplantation 84, 272–274 (2007).
Nalesnik, M. A. et al. Donor-transmitted malignancies in organ transplantation: assessment of clinical risk. Am. J. Transplant. 11, 1140–1147 (2011).
US Department of Health & Human Services. Organ Procurement and Transplantation Network: Policies [online], (2015).
Corthay, A. Does the immune system naturally protect against cancer? Front. Immunol. 5, 197–204 (2014).
Burnet, F. M. The concept of immunological surveillance. Prog. Exp. Tumour Res. 13, 1–27 (1970).
Thomas, L. On immunosurveillance in human cancer. Yale J. Biol. Med. 55, 329–333 (1982).
Kinlen, L. J. et al. Prospective study of cancer in patients with hypogammaglobulinaemia. Lancet 1, 263–266 (1985).
Mueller, B. U. & Pizzo, P. A. Cancer in children with primary or secondary immunodeficiencies. J. Paediatr. 126, 1–10 (1995).
Gatti, R. A. & Good, R. A. Occurrence of malignancy in immunodeficiency diseases. A literature review. Cancer 28, 89–98 (1971).
Salavoura, K., Kolialexi, A., Tsangaris, G. & Mavrou, A. Development of cancer in patients with primary immunodeficiencies. Anticancer Res. 28, 1263–1269 (2008).
Couzin-Frankel, J. Breakthrough of the year 2013. Cancer immunotherapy. Science 342, 1432–1433 (2013).
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD 1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).
Shankaran, V. et al. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111 (2001).
Girardi, M. et al. Regulation of cutaneous malignancy by γδ T cells. Science 294, 605–609 (2001).
Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumour escape. Nat. Immunol. 3, 991–998 (2002).
Gasser, S., Orsulic, S., Brown, E. J. & Raulet, D. H. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436, 1186–1190 (2005).
Bauer, S. et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285, 727–729 (1999).
Joseph, C. G. et al. Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science 343, 152–157 (2014).
Hojo, M. et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 397, 530–534 (1999).
Kuschal, C. et al. Skin cancer in organ transplant recipients: effects of immunosuppressive medications on DNA repair. Exp. Dermatol. 21, 2–6 (2012).
Thoms, K. M. et al. Cyclosporin A, but not everolimus, inhibits DNA repair mediated by calcineurin: implications for tumorigenesis under immunosuppression. Exp. Dermatol. 20, 232–236 (2011).
Ori, Y. et al. Effect of immunosuppressive drugs on spontaneous DNA repair in human peripheral blood mononuclear cells. Biomed. Pharmacother. 66, 409–413 (2012).
Herman, M. et al. Effect of cyclosporin A on DNA repair and cancer incidence in kidney transplant recipients. J. Lab. Clin. Med. 137, 14–20 (2001).
Weischer, M., Röcken, M. & Berneburg, M. Calcineurin inhibitors and rapamycin: cancer protection or promotion? Exp. Dermatol. 16, 385–393 (2007).
O'Donovan, P. et al. Azathioprine and UVA light generate mutagenic oxidative DNA damage. Science 309, 1871–1874 (2005).
Hofbauer, G. F. et al. Reversal of UVA skin photosensitivity and DNA damage in kidney transplant recipients by replacing azathioprine. Am. J. Transplant. 12, 218–225 (2012).
Folkman, J. The role of angiogenesis in tumour growth. Semin. Cancer Biol. 3, 65–71 (1992).
Folkman, J. What is the evidence that tumours are angiogenesis dependent? J. Natl Cancer Inst. 82, 4–6 (1990).
Guba, M. et al. Rapamycin inhibits primary and metastatic tumour growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat. Med. 8, 128–135 (2002).
Koehl, G. et al. Rapamycin protects allografts from rejection while simultaneously attacking tumours in immunosuppressed mice. Transplantation 77, 1319–1326 (2004).
Basu, A. et al. Overexpression of vascular endothelial growth factor and the development of post-transplantation cancer. Cancer Res. 68, 5689–5698 (2008).
Shihab, F. S., Bennett, W. M., Yi, H. & Andoh, T. F. Expression of vascular endothelial growth factor and its receptors Flt 1 and KDR/Flk 1 in chronic cyclosporine nephrotoxicity. Transplantation 72, 164–168 (2001).
Zhou, A. Y. & Ryeom, S. Cyclosporin A promotes tumour angiogenesis in a calcineurin-independent manner by increasing mitochondrial reactive oxygen species. Mol. Cancer Res. 12, 1663–1676 (2014).
Hernández, G. L. et al. Selective inhibition of vascular endothelial growth factor-mediated angiogenesis by cyclosporin A: roles of the nuclear factor of activated T cells and cyclooxygenase 2. J. Exp. Med. 193, 607–620 (2001).
Koehl, G. et al. MMF inhibits tumour growth and angiogenesis in vitro, but has variable anti-tumour effects in vivo possibly related to bioavailability. Transplantation 83, 607–614 (2007).
Cherikh, W. S. et al. Association of the type of induction immunosuppression with posttransplant lymphoproliferative disorder, graft survival, and patient survival after primary kidney transplantation. Transplantation 76, 1289–1293 (2003).
Paya, C. V. et al. Epstein-Barr virus-induced posttransplant lymphoproliferative disorders. Transplantation 68, 1517–1525 (1999).
Kirk, A. D. et al. Dissociation of depletional induction and posttransplant lymphoproliferative disease in kidney recipients treated with alemtuzumab. Am. J. Transplant. 7, 2619–2625 (2007).
Waldmann, H. et al. Elimination of graft-versus-host disease by in-vitro depletion of alloreactive lymphocytes with a monoclonal rat anti-human lymphocyte antibody (CAMPATH 1). Lancet 2, 483–486 (1984).
Knechtle, S. J. et al. Campath-1H induction plus Rapamycin monotherapy for renal transplantation: results of a pilot study. Am. J. Transplant. 3, 722–730 (2003).
Yao, S., Zhu, Y. & Chen, L. Advances in targeting cell surface signalling molecules for immune modulation. Nat. Rev. Drug Discov. 12, 130–146 (2013).
Eggermont, A. M., Spatz, A. & Robert, C. Cutaneous melanoma. Lancet 383, 816–827 (2014).
Nindl, I. & Rosl, F. Molecular concepts of virus infections causing skin cancer in organ transplant recipients. Am. J. Transplant. 8, 2199–2204 (2008).
Meyer, T. et al. Association of human papillomavirus infections with cutaneous tumours in immunosuppressed patients. Transpl. Int. 16, 146–153 (2003).
Martinez, O. M. & de Gruijl, F. R. Molecular and immunologic mechanisms of cancer pathogenesis in solid organ transplant recipients. Am. J. Transplant. 8, 2205–2211 (2008).
Shlomai, A., de Jong, Y. P. & Rice, C. M. Virus associated malignancies: the role of viral hepatitis in hepatocellular carcinoma. Semin. Cancer Biol. 26, 78–88 (2014).
Buell, J. F. et al. Immunosuppression and Merkel cell cancer. Transplant. Proc. 34, 1780–1781 (2002).
Spurgeon, M. E. & Lambert, P. F. Merkel cell polyomavirus: a newly discovered human virus with oncogenic potential. Virology 435, 118–130 (2013).
Chang, H. H. & Ganem, D. A unique herpesviral transcriptional programme in KSHV-infected lymphatic endothelial cells leads to mTORC1 activation and rapamycin sensitivity. Cell Host Microbe 13, 429–440 (2013).
Nichols, L. A., Adang, L. A. & Kedes, D. H. Rapamycin blocks production of KSHV/HHV8: insights into the anti-tumour activity of an immunosuppressant drug. PLoS ONE 6, e14535 (2011).
Soliman, A., Fathy, A., Khashab, S., Shaheen, N. & Soliman, M. Sirolimus conversion may suppress viral replication in hepatitis C virus-positive renal transplant candidates. Exp. Clin. Transplant. 11, 408–411 (2013).
Peng, L., Liang, D., Tong, W., Li, J. & Yuan, Z. Hepatitis C virus NS5A activates the mammalian target of rapamycin (mTOR) pathway, contributing to cell survival by disrupting the interaction between FK506-binding protein 38 (FKBP38) and mTOR. J. Biol. Chem. 285, 20870–20881 (2010).
Esser-Nobis, K., Harak, C., Schult, P., Kusov, Y. & Lohmann, V. Novel perspectives for hepatitis A virus therapy revealed by comparative analysis of hepatitis C virus and hepatitis A virus RNA replication. Hepatology 62, 397–408 (2015).
Ye, L. et al. Mycophenolate mofetil inhibits hepatitis C virus replication in human hepatic cells. Virus Res. 168, 33–40 (2012).
Holmes, M. V. et al. Prospective monitoring of Epstein-Barr virus DNA in adult renal transplant recipients during the early posttransplant period: role of mycophenolate mofetil. Transplantation 87, 852–856 (2009).
Morton, M. et al. Epstein-Barr virus infection in adult renal transplant recipients. Am. J. Transplant. 14, 1619–1629 (2014).
Sampaio, M. S., Cho, Y. W., Shah, T., Bunnapradist, S. & Hutchinson, I. V. Association of immunosuppressive maintenance regimens with posttransplant lymphoproliferative disorder in kidney transplant recipients. Transplantation 93, 73–81 (2012).
Liacini, A., Seamone, M. E., Muruve, D. A. & Tibbles, L. A. Anti-BK virus mechanisms of sirolimus and leflunomide alone and in combination: toward a new therapy for BK virus infection. Transplantation 90, 1450–1457 (2010).
Hirsch, H. H., Lu, M. & Wernli, M. Polyomavirus BK (BKV) replication in renal tubular epithelial cells is inhibited by mTOR inhibitors, but activated by tacrolimus in a pathway involving the FKBP12 [abstract 497]. Am. J. Transplant. 11, S179 (2011).
Acott, P. D., O'Regan, P. A., Lee, S. H. & Crocker, J. F. In vitro effect of cyclosporin A on primary and chronic BK polyoma virus infection in Vero E6 cells. Transpl. Infect. Dis. 10, 385–390 (2008).
Peel, M. & Scribner, A. Cyclophilin inhibitors as antiviral agents. Bioorg. Med. Chem. Lett. 23, 4485–4492 (2013).
Opelz, G. & Dohler, B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am. J. Transplant. 4, 222–230 (2004).
Ganschow, R., Schulz, T., Meyer, T., Broering, D. C. & Burdelski, M. Low-dose immunosuppression reduces the incidence of post-transplant lymphoproliferative disease in paediatric liver graft recipients. J. Paediatr. Gastroenterol. Nutr. 38, 198–203 (2004).
Dharnidharka, V. R. & Stevens, G. Risk for post-transplant lymphoproliferative disorder after polyclonal antibody induction in kidney transplantation. Paediatr. Transplant. 9, 622–626 (2005).
Magliocca, J. F. & Knechtle, S. J. The evolving role of alemtuzumab (Campath-1H) for immunosuppressive therapy in organ transplantation. Transpl. Int. 19, 705–714 (2006).
Hanaway, M. J. et al. Alemtuzumab induction in renal transplantation. N. Engl. J. Med. 364, 1909–1919 (2011).
Vincenti, F. et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am. J. Transplant. 10, 535–546 (2010).
Masson, P., Henderson, L., Chapman, J. R., Craig, J. C. & Webster, A. C. Belatacept for kidney transplant recipients. Cochrane Database Syst. Rev. 11, CD010699 (2014).
Vincenti, F. et al. Randomized phase 2b trial of tofacitinib (CP-690550) in de novo kidney transplant patients: efficacy, renal function and safety at 1 year. Am. J. Transplant. 12, 2446–2456 (2012).
Page, E. K., Dar, W. A. & Knechtle, S. J. Tolerogenic therapies in transplantation. Front. Immunol. 3, 198–211 (2012).
Page, A. et al. CD40 blockade combines with CTLA4Ig and sirolimus to produce mixed chimerism in an MHC-defined rhesus macaque transplant model. Am. J. Transplant. 12, 115–125 (2011).
Leventhal, J. et al. Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and haematopoietic stem cell transplantation. Sci. Transl. Med. 4, 124ra28 (2012).
Kawai, T. et al. HLA-mismatched renal transplantation without maintenance immunosuppression. N. Engl. J. Med. 358, 353–361 (2008).
Geissler, E. K. The ONE study compares cell therapy products in organ transplantation: introduction to a review series on suppressive monocyte-derived cells. Transplantation Res. 1, 11 (2012).
Wood, K. J., Bushell, A. & Hester, J. Regulatory immune cells in transplantation. Nat. Rev. Immunol. 12, 417–430 (2012).
Dantal, J. et al. Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet 351, 623–628 (1998).
Vivarelli, M. et al. Analysis of risk factors for tumour recurrence after liver transplantation for hepatocellular carcinoma: Key role of immunosuppression. Liver Transpl. 11, 497–503 (2005).
Kawai, T. et al. Long-term results in recipients of combined HLA-mismatched kidney and bone marrow transplantation without maintenance immunosuppression. Am. J. Transplant. 14, 1599–1611 (2014).
Scandling, J. D. et al. Chimerism, graft survival, and withdrawal of immunosuppressive drugs in HLA matched and mismatched patients after living donor kidney and haematopoietic cell transplantation. Am. J. Transplant. 15, 695–704 (2015).
Flechner, S. et al. De novo immunosuppression with mammalian target of rapamycin inhibitors and posttransplantation malignancy in focus. Transplant. Proc. 41, S42–S44 (2009).
Geissler, E. K., Schlitt, H. J. & Thomas, G. mTOR, cancer and transplantation. Am. J. Transplant. 8, 2212–2218 (2008).
Guba, M., Graeb, C., Jauch, K. W. & Geissler, E. K. Pro and anti-cancer effects of immunosuppressive agents used in organ transplantation. Transplantation 77, 1777–1782 (2004).
Dennis, P. B. et al. Mammalian TOR: a homeostatic ATP sensor. Science 294, 1102–1105 (2001).
Albert, V. & Hall, M. N. mTOR signalling in cellular and organismal energetics. Curr. Opin. Cell Biol. 33, 55–66 (2014).
Wullschleger, S., Loewith, R. & Hall, M. N. TOR signalling in growth and metabolism. Cell 124, 471–484 (2006).
Huang, S. & Houghton, P. J. Targeting mTOR signalling for cancer therapy. Curr. Opin. Pharmacol. 3, 371–377 (2003).
Jacinto, E. & Hall, M. N. Tor signalling in bugs, brain and brawn. Nat. Rev. Mol. Cell Biol. 4, 117–126 (2003).
Zarogoulidis, P. et al. mTOR pathway: A current, up-to-date mini-review (Review). Oncol. Lett. 8, 2367–2370 (2014).
Tee, A. R. Fundamental for life: mTOR orchestrates developing biological systems. Semin. Cell Dev. Biol. 36, 66–67 (2014).
Shimobayashi, M. & Hall, M. N. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat. Rev. Mol. Cell Biol. 15, 155–162 (2014).
Wells, A. D. et al. Requirement for T cell apoptosis in the induction of peripheral transplantation tolerance. Nat. Med. 5, 1303–1307 (1999).
Li, Y., Zheng, X. X., Li, X. C., Zand, M. S. & Strom, T. B. Combined co-stimulation blockade plus rapamycin but not cyclosporine produces permanent engraftment. Transplantation 66, 1387–1388 (1998).
Li, Y. et al. Blocking both signal 1 and signal 2 of T cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance. Nat. Med. 5, 1298–1302 (1999).
Battaglia, M., Stabilini, A. & Roncarolo, M. G. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 105, 4743–4748 (2005).
Zeiser, R. et al. Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells. Blood 111, 453–462 (2008).
Hendrikx, T. K. et al. Monotherapy rapamycin allows an increase of CD4+ CD25bright+ FoxP3+ T cells in renal recipients. Transpl. Int. 22, 884–891 (2009).
Taner, T., Hackstein, H., Wang, Z., Morelli, A. E. & Thomson, A. W. Rapamycin-treated, alloantigen-pulsed host dendritic cells induce Ag-specific T cell regulation and prolong graft survival. Am. J. Transplant. 5, 228–236 (2005).
Haidinger, M. et al. A versatile role of mammalian target of Rapamycin in human dendritic cell function and differentiation. J. Immunol. 185, 3919–3931 (2010).
Thomson, A. W., Turnquist, H. R. & Raimondi, G. Immunoregulation functions of mTOR inhibition. Nat. Rev. Immunol. 9, 324–337 (2009).
Pollizzi, K. N. & Powell, J. D. Regulation of T cells by mTOR: the known knowns and the known unknowns. Trends Immunol. 36, 13–20 (2015).
Delgoffe, G. M. et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signalling by mTORC1 and mTORC2. Nat. Immunol. 12, 295–303 (2011).
Turner, A. P. et al. Sirolimus enhances the magnitude and quality of viral-specific CD8+ T cell responses to vaccinia virus vaccination in rhesus macaques. Am. J. Transplant. 11, 613–618 (2011).
Araki, K. et al. mTOR regulates memory CD8 T cell differentiation. Nature 460, 108–112 (2009).
Rao, R. R., Li, Q., Odunsi, K. & Shrikant, P. A. The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T bet and Eomesodermin. Immunity 32, 67–78 (2010).
Amiel, E. et al. Inhibition of mechanistic target of rapamycin promotes dendritic cell activation and enhances therapeutic autologous vaccination in mice. J. Immunol. 189, 2151–2158 (2012).
Rovira, J. et al. A colour-coded reporter model to study the effect of immunosuppressants on CD8+ T cell memory in antitumour and alloimmune responses. Transplantation 95, 54–62 (2013).
Li, Q. et al. A central role for mTOR kinase in homeostatic proliferation induced CD8+ T cell memory and tumour immunity. Immunity 34, 541–553 (2011).
Majewski, M. et al. Immunosuppressive TOR kinase inhibitor everolimus (RAD) suppresses growth of cells derived from posttransplant lymphoproliferative disorder at allograft-protecting doses. Transplantation 75, 1710–1717 (2003).
Majewski, M. et al. The immunosuppressive macrolide RAD inhibits growth of human Epstein-Barr virus-transformed B lymphocytes in vitro and in vivo: A potential approach to prevention and treatment of posttransplant lymphoproliferative disorders. Proc. Natl Acad. Sci. USA 97, 4285–4290 (2000).
Spangle, J. M. & Münger, K. The human papillomavirus type 16 E6 oncoprotein activates mTORC1 signalling and increases protein synthesis. J. Virol. 84, 9398–9407 (2010).
Ashrafi, F., Shahidi, S., Ebrahimi, Z. & Mortazavi, M. Outcome of rapamycin therapy for post-transplant-lymphoproliferative disorder after kidney transplantation: case series. Int. J. Haematol. Oncol. Stem Cell Res. 9, 26–32 (2015).
Petroulakis, E., Mamane, Y., Le Bacquer, O., Shahbazian, D. & Sonenberg, N. mTOR signalling: implications for cancer and anticancer therapy. Br. J. Cancer 94, 195–199 (2006).
Guertin, D. A. & Sabatini, D. M. Defining the role of mTOR in cancer. Cancer Cell 12, 9–22 (2007).
Bjornsti, M. A. & Houghton, P. J. The tor pathway: a target for cancer therapy. Nat. Rev. Cancer 4, 335–348 (2004).
Phung, T. L. et al. Pathological angiogenesis is induced by sustained Akt signalling and inhibited by rapamycin. Cancer Cell 10, 159–170 (2006).
Campistol, J. M., Gutierrez-Dalmau, A. & Torregrosa, J. V. Conversion to sirolimus: a successful treatment for posttransplantation Kaposi's sarcoma. Transplantation 77, 760–762 (2004).
Stallone, G. et al. Sirolimus for Kaposi's sarcoma in renal-transplant recipients. N. Engl. J. Med. 352, 1317–1323 (2005).
Huber, S. et al. Inhibition of the mammalian target of rapamycin impedes lymphangiogenesis. Kidney Int. 71, 771–777 (2007).
Campistol, J. M. Minimizing the risk of posttransplant malignancy. Transplantation 87, S19–S22 (2009).
Valantine, H. Is there a role for proliferation signal/mTOR inhibitors in the prevention and treatment of de novo malignancies after heart transplantation? Lessons learned from renal transplantation and oncology. J. Heart Lung Transplant. 26, 557–564 (2007).
Webster, A. C., Lee, V. W., Chapman, J. R. & Craig, J. C. Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials. Transplantation 81, 1234–1248 (2006).
Ekberg, H. et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N. Engl. J. Med. 357, 2562–2575 (2007).
Schnitzbauer, A. A., Schlitt, H. J. & Geissler, E. K. Influence of immunosuppressive drugs on the recurrence of hepatocellular carcinoma after liver transplantation: a gap between basic science and clinical evidence. Transplantation 91, 1173–1176 (2011).
Hoogendijk-van den Akker J. M. et al. Two-year randomized controlled prospective trial converting treatment of stable renal transplant recipients with cutaneous invasive squamous cell carcinomas to sirolimus. J. Clin. Oncol. 31, 1317–1323 (2013).
Euvrard, S. et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N. Engl. J. Med. 367, 329–339 (2012).
Campbell, S. B., Walker, R., Tai, S. S., Jiang, Q. & Russ, G. R. Randomized controlled trial of sirolimus for renal transplant recipients at high risk for nonmelanoma skin cancer. Am. J. Transplant. 12, 1146–1156 (2012).
Detroyer, D. et al. Resolution of diffuse skin and systemic Kaposi's sarcoma in a renal transplant recipient after introduction of everolimus: a case report. Transpl. Infect. Dis. 17, 303–307 (2015).
Kuang, E., Fu, B., Liang, Q., Myoung, J. & Zhu, F. Phosphorylation of eukaryotic translation initiation factor 4B (EIF4B) by open reading frame 45/p90 ribosomal S6 kinase (ORF45/RSK) signalling axis facilitates protein translation during Kaposi sarcoma-associated herpesvirus (KSHV) lytic replication. J. Biol. Chem. 286, 41171–41182 (2011).
Mourah, S. et al. Paradoxical simultaneous regression and progression of lesions in a phase ii study of everolimus in classic kaposi's sarcoma. Br. J. Dermatol. http://dx.doi.org/10.1111/bjd.13897 (2015).
Menon, K. V., Hakeem, A. R. & Heaton, N. D. Meta-analysis: recurrence and survival following the use of sirolimus in liver transplantation for hepatocellular carcinoma. Aliment. Pharmacol. Ther. 37, 411–419 (2013).
Liang, W. et al. Sirolimus-based immunosuppression in liver transplantation for hepatocellular carcinoma: a meta-analysis. Liver Transpl. 18, 62–69 (2012).
Chinnakotla, S. et al. Impact of sirolimus on the recurrence of hepatocellular carcinoma after liver transplantation. Liver Transpl. 15, 1834–1842 (2009).
Toso, C., Merani, S., Bigam, D. L., Shapiro, A. M. & Kneteman, N. M. Sirolimus-based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma. Hepatology 51, 1237–1243 (2010).
Zimmerman, M. A. et al. Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma. Liver Transpl. 14, 633–638 (2008).
Kneteman, N. M. et al. Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma. Liver Transpl. 10, 1301–1311 (2004).
Schnitzbauer, A. A. et al. A prospective randomised, open-labelled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma. BMC Cancer 10, 190 (2010).
Geissler, E. K. et al. Sirolimus use in liver transplant recipients with hepatocellular carcinoma: a randomised, multi-centre, open-label phase 3 trial. Transplantation (in press).
Zhu, A. X. et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE 1 randomized clinical trial. JAMA 312, 57–67 (2014).
Knoll, G. A. et al. Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data. BMJ 349, g6679 (2014).
Yanik, E. L. et al. Sirolimus use and cancer incidence among US kidney transplant recipients. Am. J. Transplant. 15, 129–136 (2015).
Webster, A. C., Wong, G., Craig, J. C. & Chapman, J. R. Managing cancer risk and decision making after kidney transplantation. Am. J. Transplant. 8, 2185–2191 (2008).
Breyer, B. N., Whitson, J. M., Freise, C. E. & Meng, M. V. Prostate cancer screening and treatment in the transplant population: current status and recommendations. J. Urol. 181, 2018–2025 (2009).
Wong, G., Chapman, J. R. & Craig, J. C. Cancer screening in renal transplant recipients: what is the evidence? Clin. J. Am. Soc. Nephrol. 3 (Suppl. 2), S87–S100 (2008).
Kohli, A., Shaffer, A., Sherman, A. & Kottilil, S. Treatment of hepatitis C: a systematic review. JAMA 312, 631–640 (2014).
Lens, S., Marino, Z. & Forns, X. Efficacy of new direct acting antivirals in transplant recipients and patients with advanced disease. Dig. Liver Dis. 46, S197–S205 (2014).
Vinzón, S. E. et al. Protective vaccination against papillomavirus-induced skin tumours under immunocompetent and immunosuppressive conditions: a preclinical study using a natural outbred animal model. PLoS Pathog. 10, e1003924 (2014).
US Renal Data System. USRDS 2012 annual data report: atlas of chronic kidney disease and end-stage renal disease in the United States [online], (2012).
Australia and New Zealand Dialysis and Transplant Registry. ANZDATA Registry Report 2010 [online], (2010).
Haynes, R. et al. Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomised trial. Lancet 384, 1684–1690 (2014).
Durrbach, A. et al. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study). Am. J. Transplant. 10, 547–557 (2010).
Hudes, G. et al. Temsirolimus, interferon α, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356, 2271–2281 (2007).
Motzer, R. J. et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372, 449–456 (2008).
Zhang, L. et al. Mammalian target of rapamycin complex 1 orchestrates invariant NKT cell differentiation and effector function. J. Immunol. 193, 1759–1765 (2014).
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E.K.G. has previously received research funding and speaking honoraria from Pfizer Inc.
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Geissler, E. Post-transplantation malignancies: here today, gone tomorrow?. Nat Rev Clin Oncol 12, 705–717 (2015). https://doi.org/10.1038/nrclinonc.2015.186
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DOI: https://doi.org/10.1038/nrclinonc.2015.186
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