Antigen spreading-induced CD8+T cells confer protection against the lethal challenge of wild-type malignant mesothelioma by eliminating myeloid-derived suppressor cells
Zhe Yu, Zhiwu Tan, Boon Kiat Lee, Jiansong Tang, Xilin Wu, Ka-Wai Cheung, Nathan Tin Lok Lo, Kwan Man, Li Liu, Zhiwei Chen, Zhe Yu, Zhiwu Tan, Boon Kiat Lee, Jiansong Tang, Xilin Wu, Ka-Wai Cheung, Nathan Tin Lok Lo, Kwan Man, Li Liu, Zhiwei Chen
Abstract
A key focus in cancer immunotherapy is to investigate the mechanism of efficacious vaccine responses. Using HIV-1 GAG-p24 in a model PD1-based DNA vaccine, we recently reported that vaccine-elicited CD8+ T cells conferred complete prevention and therapeutic cure of AB1-GAG malignant mesothelioma in immunocompetent BALB/c mice. Here, we further investigated the efficacy and correlation of protection on the model vaccine-mediated antigen spreading against wild-type AB1 (WT-AB1) mesothelioma. We found that this vaccine was able to protect mice completely from three consecutive lethal challenges of AB1-GAG mesothelioma. Through antigen spreading these animals also developed tumor-specific cytotoxic CD8+ T cells, but neither CD4+ T cells nor antibodies, rejecting WT-AB1 mesothelioma. A majority of these protected mice (90%) were also completely protected against the lethal WT-AB1 challenge. Adoptive cell transfer experiments further demonstrated that antigen spreading-induced CD8+ T cells conferred efficacious therapeutic effects against established WT-AB1 mesothelioma and prevented the increase of exhausted PD-1+ and Tim-3+ CD8+ T cells. A significant inverse correlation was found between the frequency of functional PD1-Tim3- CD8+ T cells and that of MDSCs or tumor mass in vivo. Mechanistically, we found that WT-AB1 mesothelioma induced predominantly polymorphonuclear (PMN) MDSCs in vivo. In co-cultures with efficacious CD8+ T cells, a significant number of PMN-MDSCs underwent apoptosis in a dose-dependent way. Our findings indicate that efficacious CD8+ T cells capable of eliminating both tumor cells and MDSCs are likely necessary for fighting wild-type malignant mesothelioma.
Keywords: CD8+T cells; Immune response; Immunity; Immunology and Microbiology Section; MDSCs; antigen spreading; mesothelioma; vaccination.
Conflict of interest statement
CONFLICTS OF INTEREST
No potential conflicts of interest were disclosed.
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References
- Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nature reviews Cancer. 2012;12:237–251.
- Restifo NP, Dudley ME, Rosenberg SA. Adoptive immunotherapy for cancer: harnessing the T cell response. Nature reviews Immunology. 2012;12:269–281.
- Coulie PG, Van den Eynde BJ, van der Bruggen P, Boon T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nature reviews Cancer. 2014;14:135–146.
- Barry M, Bleackley RC. Cytotoxic T lymphocytes: all roads lead to death. Nature reviews Immunology. 2002;2:401–409.
- Tan Z, Zhou J, Cheung AK, Yu Z, Cheung KW, Liang J, Wang H, Lee BK, Man K, Liu L, Yuen KY, Chen Z. Vaccine-elicited CD8+ T cells cure mesothelioma by overcoming tumor-induced immunosuppressive environment. Cancer research. 2014;74:6010–21.
- Zhou JY, Cheung AKL, Tan ZW, Wang HB, Yu WB, Du YH, Kang YX, Lu XF, Liu L, Yuen KY, Chen ZW. PD1-based DNA vaccine amplifies HIV-1 GAG-specific CD8(+) T cells in mice. J Clin Invest. 2013;123:2629–2642.
- Zhu Y, Ju S, Chen E, Dai S, Li C, Morel P, Liu L, Zhang X, Lu B. T-bet and eomesodermin are required for T cell-mediated antitumor immune responses. Journal of immunology. 2010;185:3174–3183.
- Lu T, Ramakrishnan R, Altiok S, Youn JI, Cheng P, Celis E, Pisarev V, Sherman S, Sporn MB, Gabrilovich D. Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice. J Clin Invest. 2011;121:4015–4029.
- Lindau D, Gielen P, Kroesen M, Wesseling P, Adema GJ. The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells. Immunology. 2013;138:105–115.
- Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nature Reviews Immunology. 2009;9:162–174.
- Cheever MA, Allison JP, Ferris AS, Finn OJ, Hastings BM, Hecht TT, Mellman I, Prindiville SA, Viner JL, Weiner LM, Matrisian LM. The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research. Clinical cancer research : an official journal of the American Association for Cancer Research. 2009;15:5323–5337.
- Khaled YS, Ammori BJ, Elkord E. Myeloid-derived suppressor cells in cancer: recent progress and prospects. Immunol Cell Biol. 2013;91:493–502.
- Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nature reviews Immunology. 2012;12:253–268.
- Kreiter S, Vormehr M, van de Roemer N, Diken M, Lower M, Diekmann J, Boegel S, Schrors B, Vascotto F, Castle JC, Tadmor AD, Schoenberger SP, Huber C, Tureci O, Sahin U. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature. 2015;520:692–696.
- Buckwalter MR, Srivastava PK. Mechanism of dichotomy between CD8+ responses elicited by apoptotic and necrotic cells. Cancer immunity. 2013;13:2.
- Storkus WJ, Falo LD., Jr A ‘good death’ for tumor immunology. Nature medicine. 2007;13:28–30.
- Zhou J, Cheung AK, Liu H, Tan Z, Tang X, Kang Y, Du Y, Wang H, Liu L, Chen Z. Potentiating functional antigen-specific CD8(+) T cell immunity by a novel PD1 isoform-based fusion DNA vaccine. Molecular therapy : the journal of the American Society of Gene Therapy. 2013;21:1445–1455.
- Inoue H, Tani K. Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments. Cell death and differentiation. 2014;21:39–49.
- Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nature reviews Cancer. 2012;12(4):278–287.
- Schreiber H, Ward PL, Rowley DA, Stauss HJ. Unique tumor-specific antigens. Annual review of immunology. 1988;6:465–483.
- Reits EA, Hodge JW, Herberts CA, Groothuis TA, Chakraborty M, Wansley EK, Camphausen K, Luiten RM, de Ru AH, Neijssen J, Griekspoor A, Mesman E, Verreck FA, Spits H, Schlom J, van Veelen P, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. The Journal of experimental medicine. 2006;203:1259–1271.
- Corbiere V, Chapiro J, Stroobant V, Ma W, Lurquin C, Lethe B, van Baren N, Van den Eynde BJ, Boon T, Coulie PG. Antigen spreading contributes to MAGE vaccination-induced regression of melanoma metastases. Cancer research. 2011;71:1253–1262.
- Condamine T, Kumar V, Ramachandran IR, Youn JI, Celis E, Finnberg N, El-Deiry WS, Winograd R, Vonderheide RH, English NR, Knight SC, Yagita H, McCaffrey JC, Antonia S, Hockstein N, Witt R, et al. ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. J Clin Invest. 2014;124:2626–2639.
- Sinha P, Chornoguz O, Clements VK, Artemenko KA, Zubarev RA, Ostrand-Rosenberg S. Myeloid-derived suppressor cells express the death receptor Fas and apoptose in response to T cell-expressed FasL. Blood. 2011;117:5381–5390.
- Drake CG, Jaffee E, Pardoll DM. Mechanisms of immune evasion by tumors. Adv Immunol. 2006;90:51–81.
- Poschke I, Mougiakakos D, Kiessling R. Camouflage and sabotage: tumor escape from the immune system. Cancer Immunol Immun. 2011;60:1161–1171.
- Whiteside TL, Mandapathil M, Szczepanski M, Szajnik M. Mechanisms of tumor escape from the immune system: Adenosine-producing Treg, exosomes and tumor-associated TLRs. B Cancer. 2011;98:E25–E31.
- Pulido J, Kottke T, Thompson J, Galivo F, Wongthida P, Diaz RM, Rommelfanger D, Ilett E, Pease L, Pandha H, Harrington K, Selby P, Melcher A, Vile R. Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma. Nat Biotechnol. 2012;30:336–343.
- Kottke T, Errington F, Pulido J, Galivo F, Thompson J, Wongthida P, Diaz RM, Chong H, Ilett E, Chester J, Pandha H, Harrington K, Selby P, Melcher A, Vile R. Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors. Nature medicine. 2011;17:854–U223.
- Finn OJ. Cancer vaccines: Between the idea and the reality. Nature Reviews Immunology. 2003;3:630–641.
- Vanderlugt CL, Miller SD. Epitope spreading in immune-mediated diseases: implications for immunotherapy. Nature reviews Immunology. 2002;2:85–95.
- Disis ML, Gooley TA, Rinn K, Davis D, Piepkorn M, Cheever MA, Knutson KL, Schiffman K. Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines. J Clin Oncol. 2002;20:2624–2632.
- Butterfield LH, Ribas A, Dissette VB, Amarnani SN, Vu HT, Oseguera D, Wang HJ, Elashoff RM, McBride WH, Mukherji B, Cochran AJ, Glaspy JA, Economou JS. Determinant spreading associated with clinical response in dendritic cell-based immunotherapy for malignant melanoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2003;9:998–1008.
- Tagawa M, Tada Y, Shimada H, Hiroshima K. Gene therapy for malignant mesothelioma: current prospects and challenges. Cancer gene therapy. 2013;20:150–156.
- Zhong S, Malecek K, Johnson LA, Yu Z, Vega-Saenz de Miera E, Darvishian F, McGary K, Huang K, Boyer J, Corse E, Shao Y, Rosenberg SA, Restifo NP, Osman I, Krogsgaard M. T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy. Proceedings of the National Academy of Sciences of the United States of America. 2013;110:6973–6978.
- Neveu B, Debeaupuis E, Echasserieau K, le Moullac-Vaidye B, Gassin M, Jegou L, Decalf J, Albert M, Ferry N, Gournay J, Houssaint E, Bonneville M, Saulquin X. Selection of high-avidity CD8 T cells correlates with control of hepatitis C virus infection. Hepatology. 2008;48:713–722.
- Weiss JM, Subleski JJ, Back T, Chen X, Watkins SK, Yagita H, Sayers TJ, Murphy WJ, Wiltrout RH. Regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment undergo Fas-dependent cell death during IL-2/alphaCD40 therapy. J Immunol. 2014;192:5821–5829.
- Chuang CM, Monie A, Wu A, Pai SI, Hung CF. Combination of viral oncolysis and tumor-specific immunity to control established tumors. Clinical cancer research : an official journal of the American Association for Cancer Research. 2009;15:4581–4588.
- Bracci L, Moschella F, Sestili P, La Sorsa V, Valentini M, Canini I, Baccarini S, Maccari S, Ramoni C, Belardelli F, Proietti E. Cyclophosphamide enhances the antitumor efficacy of adoptively transferred immune cells through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and specific tumor infiltration. Clinical Cancer Research. 2007;13:644–653.
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