Cancer Exome Analysis Reveals a T Cell Dependent Mechanism of Cancer Immunoediting

By H. Matsushita, M. Vesely, Daniel C. Koboldt, C. Rickert, Ravi Uppaluri, Vincent J. Magrini, C. Arthur, J. White, Ye Chen, L. Shea and 9 more. Nature, 2012

1,252 citations recorded by the source corpus.

Cancer immunoediting, the process by which the immune system controls tumour outgrowth and shapes tumour immunogenicity, is comprised of three phases: elimination, equilibrium and escape. Although many immune components that participate in this process are known, its underlying mechanisms remain poorly defined. A central tenet of cancer immunoediting is that T-cell recognition of tumour antigens drives the immunological destruction or sculpting of a developing cancer. However, our current understanding of tumour antigens comes largely from analyses of cancers that develop in immunocompetent hosts and thus may have already been edited. Little is known about the antigens expressed in nascent tumour cells, whether they are sufficient to induce protective antitumour immune responses or whether their expression is modulated by the immune system. Here, using massively parallel sequencing, we characterize expressed mutations in highly immunogenic methylcholanthrene-induced sarcomas derived from immunodeficient Rag2−/− mice that phenotypically resemble nascent primary tumour cells. Using class I prediction algorithms, we identify mutant spectrin-β2 as a potential rejection antigen of the d42m1 sarcoma and validate this prediction by conventional antigen expression cloning and detection. We also demonstrate that cancer immunoediting of d42m1 occurs via a T-cell-dependent immunoselection process that promotes outgrowth of pre-existing tumour cell clones lacking highly antigenic mutant spectrin-β2 and other potential strong antigens. These results demonstrate that the strong immunogenicity of an unedited tumour can be ascribed to expression of highly antigenic mutant proteins and show that outgrowth of tumour cells that lack these strong antigens via a T-cell-dependent immunoselection process represents one mechanism of cancer immunoediting.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/1cdf7f6201c71f79ab40d9e18e25189e438853b7

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Citations in the corpus

Immune escape mechanisms as a guide for cancer immunotherapy (2014, background): “7 and other non-immunogenic cancers, such as PDAC, showing a low mutation rate (15, 16).”
T Cell Dysfunction in Cancer (2018, background): “These alterations distinguish cancer cells from normal cells, thereby frequently prompting the induction of tumor-reactive T cell responses in both mouse models and cancer patients (Castle et al., 2012; Matsushita et al., 2012; Robbins et al., 2013; van Rooij et al., 2013).”