Abstract
The recent demonstration that cancer immunotherapy extends patient survival has reinvigorated interest in elucidating the role of immunity in tumour pathogenesis. Experimental mouse tumour models have provided key mechanistic insights into host antitumour immune responses, and these have guided the development of novel treatment strategies. To accelerate the translation of these findings into clinical benefits, investigators need to gain a better understanding of the strengths and limitations of mouse model systems as tools for deciphering human antitumour immune responses.
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References
Keir, M. E., Butte, M. J., Freeman, G. J. & Sharpe, A. H. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26, 677–704 (2008).
Kantoff, P. W. et al. Overall survival analysis of a Phase II randomized controlled trial of a poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J. Clin. Oncol. 28, 1099–1105 (2010).
Brichard, V. G. & Lejeune, D. GSK's antigen-specific cancer immunotherapy programme: pilot results leading to Phase III clinical development. Vaccine 25 (Suppl. 2), B61–B71 (2007).
Dougan, M. & Dranoff, G. Immune therapy for cancer. Annu. Rev. Immunol. 27, 83–117 (2009).
Ostrand-Rosenberg, S. Animal models of tumor immunity, immunotherapy and cancer vaccines. Curr. Opin. Immunol. 16, 143–150 (2004).
Prehn, R. T. & Main, J. M. Immunity to methylcholanthrene-induced sarcomas. J. Natl Cancer Inst. 18, 769–778 (1957).
Klein, G., Sjogren, H. O., Klein, E. & Hellstrom, K. E. Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochtonous host. Cancer Res. 20, 1561–1572 (1960).
Old, L., Clarke, D. & Benacerraf, B. Effect of bacillus Calmette-Guerin (BCG) infection on transplanted tumors in the mouse. Nature 184, 291–292 (1959).
Van Pel, A. & Boon, T. Protection against a non-immunogenic mouse leukemia by an immunogenic variant obtained by mutagenesis. Proc. Natl Acad. Sci. USA 79, 4718–4722 (1982).
Basombrio, M. A. Search for common antigenicity among twenty-five sarcomas induced by methylcholanthrene. Cancer Res. 30, 2458–2462 (1970).
Craft, N. et al. Bioluminescent imaging of melanoma in live mice. J. Invest. Dermatol. 125, 159–165 (2005).
Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nature Med. 13, 54–61 (2007).
Apetoh, L. et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nature Med. 13, 1050–1059 (2007).
Dranoff, G. et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc. Natl Acad. Sci. USA 90, 3539–3543 (1993).
Gilboa, E. The makings of a tumor rejection antigen. Immunity 11, 263–270 (1999).
Hanson, H. L. et al. Eradication of established tumors by CD8+ T cell adoptive immunotherapy. Immunity 13, 265–276 (2000).
Overwijk, W. W. et al. Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. J. Exp. Med. 198, 569–580 (2003).
Xie, Y. et al. Naive tumor-specific CD4+ T cells differentiated in vivo eradicate established melanoma. J. Exp. Med. 207, 651–667 (2010).
Cavallo, F., Offringa, R., van der Burg, S. H., Forni, G. & Melief, C. J. Vaccination for treatment and prevention of cancer in animal models. Adv. Immunol. 90, 175–213 (2006).
Zhang, B., Karrison, T., Rowley, D. A. & Schreiber, H. IFN-γ- and TNF-dependent bystander eradication of antigen-loss variants in established mouse cancers. J. Clin. Invest. 118, 1398–1404 (2008).
Klebanoff, C. A. et al. Determinants of successful CD8+ T-cell adoptive immunotherapy for large established tumors in mice. Clin. Cancer Res. 17, 5343–5352 (2011).
Korman, A., Peggs, K. & Allison, J. P. Checkpoint blockade in cancer immunotherapy. Adv. Immunol. 90, 293–335 (2006).
Quezada, S. A., Peggs, K. S., Curran, M. A. & Allison, J. P. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J. Clin. Invest. 116, 1935–1945 (2006).
Hodi, F. S. et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc. Natl Acad. Sci. USA 105, 3005–3010 (2008).
Fu, T., He, Q. & Sharma, P. The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti-CTLA-4 therapy. Cancer Res. 71, 5445–5454 (2011).
Liakou, C. I. et al. CTLA-4 blockade increases IFNγ-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc. Natl Acad. Sci. USA 105, 14987–14992 (2008).
van Elsas, A., Hurwitz, A. & Allison, J. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J. Exp. Med. 190, 355–366 (1999).
Berger, R. et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin. Cancer Res. 14, 3044–3051 (2008).
Brahmer, J. R. et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28, 3167–3175 (2010).
Li, B. et al. Anti-programmed death-1 synergizes with granulocyte macrophage colony-stimulating factor-secreting tumor cell immunotherapy providing therapeutic benefit to mice with established tumors. Clin. Cancer Res. 15, 1623–1634 (2009).
Melero, I. et al. Palettes of vaccines and immunostimulatory monoclonal antibodies for combination. Clin. Cancer Res. 15, 1507–1509 (2009).
Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).
Vesely, M. D., Kershaw, M. H., Schreiber, R. D. & Smyth, M. J. Natural innate and adaptive immunity to cancer. Annu. Rev. Immunol. 29, 235–271 (2011).
Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008).
Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).
Qian, B. Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011).
Yu, H., Kortylewski, M. & Pardoll, D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nature Rev. Immunol. 7, 41–51 (2007).
Marigo, I. et al. Tumor-induced tolerance and immune suppression depend on the C/EBPβ transcription factor. Immunity 32, 790–802 (2010).
Schioppa, T. et al. B regulatory cells and the tumor-promoting actions of TNF-α during squamous carcinogenesis. Proc. Natl Acad. Sci. USA 108, 10662–10667 (2011).
Rabinovich, G. A., Gabrilovich, D. & Sotomayor, E. M. Immunosuppressive strategies that are mediated by tumor cells. Annu. Rev. Immunol. 25, 267–296 (2007).
Zou, W. Regulatory T cells, tumour immunity and immunotherapy. Nature Rev. Immunol. 6, 295–307 (2006).
DuPage, M. et al. Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression. Cancer Cell 19, 72–85 (2011).
Dougan, M. et al. A dual role for the immune response in a mouse model of inflammation-associated lung cancer. J. Clin. Invest. 121, 2436–2446 (2011).
Hurwitz, A. A. et al. Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade. Cancer Res. 60, 2444–2448 (2000).
Ercolini, A. M. et al. Recruitment of latent pools of high-avidity CD8+ T cells to the antitumor immune response. J. Exp. Med. 201, 1591–1602 (2005).
Rovero, S. et al. DNA vaccination against rat Her-2/Neu p185 more effectively inhibits carcinogenesis than transplantable carcinomas in transgenic BALB/c mice. J. Immunol. 165, 5133–5142 (2000).
Reilly, R. et al. The collaboration of both humoral and cellular HER-2/neu-targeted immune responses is required for the complete eradication of HER-2/neu-expressing tumors. Cancer Res. 61, 880–883 (2001).
Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203–213 (2003).
Galon, J. et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006).
Wahlin, B. E. et al. A unifying microenvironment model in follicular lymphoma: outcome is predicted by programmed death-1-positive, regulatory, cytotoxic, and helper T cells and macrophages. Clin. Cancer Res. 16, 637–650 (2010).
Ruffell, B. et al. Leukocyte composition of human breast cancer. Proc. Natl Acad. Sci. USA 8 Aug 2011 (doi:10.1073/pnas.1104303108).
Qian, B. Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).
Ferrone, C. & Dranoff, G. Dual roles for immunity in gastrointestinal cancers. J. Clin. Oncol. 28, 4045–4051 (2010).
Legrand, N. et al. Humanized mice for modeling human infectious disease: challenges, progress, and outlook. Cell Host Microbe 6, 5–9 (2009).
Pedroza-Gonzalez, A. et al. Thymic stromal lymphopoietin fosters human breast tumor growth by promoting type 2 inflammation. J. Exp. Med. 208, 479–490 (2011).
Carpenito, C. et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc. Natl Acad. Sci. USA 106, 3360–3365 (2009).
Kalos, M. et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 3, 95ra73 (2011).
Higano, C. S. et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer 115, 3670–3679 (2009).
Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 (2010).
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).
Acknowledgements
Glenn Dranoff is supported by grants from the US National Cancer Institute, the Leukemia and Lymphoma Society, the Melanoma Research Alliance, the Alliance for Cancer Gene Therapy and the Research Foundation for the Treatment of Ovarian Cancer.
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Dranoff, G. Experimental mouse tumour models: what can be learnt about human cancer immunology?. Nat Rev Immunol 12, 61–66 (2012). https://doi.org/10.1038/nri3129
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DOI: https://doi.org/10.1038/nri3129
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