@article{785d4b62aa984f478f7a9d4ccc8f9286,
title = "Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting",
abstract = "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.",
author = "Hirokazu Matsushita and Vesely, {Matthew D.} and Koboldt, {Daniel C.} and Rickert, {Charles G.} and Ravindra Uppaluri and Magrini, {Vincent J.} and Arthur, {Cora D.} and White, {J. Michael} and Chen, {Yee Shiuan} and Shea, {Lauren K.} and Jasreet Hundal and Wendl, {Michael C.} and Ryan Demeter and Todd Wylie and Allison, {James P.} and Smyth, {Mark J.} and Old, {Lloyd J.} and Mardis, {Elaine R.} and Schreiber, {Robert D.}",
note = "Funding Information: Acknowledgements We are grateful to J. Archambault for expert technical assistance, T. H. Hansen (Washington University) for providing MHC class I antibodies, S. Horvath and P. M. Allen (Washington University) for synthesizing MHC class I peptides, the National Institutes of Health (NIH) Tetramer Core Facility for producing MHC class I tetramers, and T. S. Stappenbeck (Washington University) for technical help in recovering frozen tumour samples. We also thank E. Unanue, P. M. Allen and J. Bui for criticisms and comments, all members of the Schreiber laboratory for discussions, and the many members of The Genome Institute at Washington University School of Medicine, especially L. Ding for her insights into our analytical approaches. This work was supported by grants to R.D.S. from the National Cancer Institute, the Ludwig Institute for Cancer Research, the Cancer Research Institute, and the WWWW Foundation; and to E.R.M. from the NationalHuman Genome Research Institute. M.D.V. is supported by a pre-doctoral fellowship from the Cancer Research Institute. J.P.A. is supported by the Howard Hughes Medical Institute and the Ludwig Center for Cancer Immunotherapy; M.J.S. by the National Health and Medical Research Council of Australia (NH&MRC) and from the Association for International Cancer Research; and L.J.O. by the Ludwig Institute for Cancer Research and the Cancer Research Institute.",
year = "2012",
month = feb,
day = "16",
doi = "10.1038/nature10755",
language = "English",
volume = "482",
pages = "400--404",
journal = "Nature",
issn = "0028-0836",
number = "7385",
}