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Expression of tumour-specific antigens underlies cancer immunoediting

Abstract

Cancer immunoediting is a process by which immune cells, particularly lymphocytes of the adaptive immune system, protect the host from the development of cancer and alter tumour progression by driving the outgrowth of tumour cells with decreased sensitivity to immune attack1,2. Carcinogen-induced mouse models of cancer have shown that primary tumour susceptibility is thereby enhanced in immune-compromised mice, whereas the capacity for such tumours to grow after transplantation into wild-type mice is reduced2,3. However, many questions about the process of cancer immunoediting remain unanswered, in part because of the known antigenic complexity and heterogeneity of carcinogen-induced tumours4. Here we adapted a genetically engineered, autochthonous mouse model of sarcomagenesis to investigate the process of cancer immunoediting. This system allows us to monitor the onset and growth of immunogenic and non-immunogenic tumours induced in situ that harbour identical genetic and histopathological characteristics. By comparing the development of such tumours in immune-competent mice with their development in mice with broad immunodeficiency or specific antigenic tolerance, we show that recognition of tumour-specific antigens by lymphocytes is critical for immunoediting against sarcomas. Furthermore, primary sarcomas were edited to become less immunogenic through the selective outgrowth of cells that were able to escape T lymphocyte attack. Loss of tumour antigen expression or presentation on major histocompatibility complex I was necessary and sufficient for this immunoediting process to occur. These results highlight the importance of tumour-specific-antigen expression in immune surveillance, and potentially, immunotherapy.

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Figure 1: Sarcoma formation in immunodeficient compared to wild-type mice occurs with increased penetrance and reduced latency.
Figure 2: Functional T-cell responses are generated against antigens expressed in sarcomas.
Figure 3: Cancer immunoediting phenotypes require the presence of potent T-cell antigens.
Figure 4: Immunoediting occurs by selecting for tumour cells that do not express targeted antigens.

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Acknowledgements

We thank M. M. Winslow and A. G. DuPage for critical reading of this manuscript. This work was supported by grant 1 U54 CA126515-01 from the NIH, and partially by Cancer Center Support (core) grant P30-CA14051 from the National Cancer Institute and the Margaret A. Cunningham Immune Mechanisms in Cancer Research Fellowship Award (M.D.) from the John D. Proctor Foundation. T.J. is a Howard Hughes Investigator and a Daniel K. Ludwig Scholar.

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M.D. and T.J. designed the study. M.D. performed all experiments with assistance from C.M. and L.M.S. A.F.C. provided reagents and conceptual advice. M.D. and T.J. wrote the manuscript.

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Correspondence to Tyler Jacks.

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The authors declare no competing financial interests.

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DuPage, M., Mazumdar, C., Schmidt, L. et al. Expression of tumour-specific antigens underlies cancer immunoediting. Nature 482, 405–409 (2012). https://doi.org/10.1038/nature10803

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