Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy

作者：Mihaela Angelova, Pornpimol Charoentong, Hubert Hackl, Maria L Fischer, René Snajder, Anne Krogsdam, Maximilian J. Waldner, Gabriela Bindea, Bernhard Mlecnik, Jérôme Galon, Zlatko Trajanoski · 发表于：Genome biology · 年份：2015 · DOI：10.1186/s13059-015-0620-6 · 被引用次数：555 · 研究领域：Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses、T-cell and B-cell Immunology

BACKGROUND: While large-scale cancer genomic projects are comprehensively characterizing the mutational spectrum of various cancers, so far little attention has been devoted to either define the antigenicity of these mutations or to characterize the immune responses they elicit. Here we present a strategy to characterize the immunophenotypes and the antigen-ome of human colorectal cancer. RESULTS: We apply our strategy to a large colorectal cancer cohort (n = 598) and show that subpopulations of tumor-infiltrating lymphocytes are associated with distinct molecular phenotypes. The characterization of the antigenome shows that a large number of cancer-germline antigens are expressed in all patients. In contrast, neo-antigens are rarely shared between patients, indicating that cancer vaccination requires individualized strategy. Analysis of the genetic basis of the tumors reveals distinct tumor escape mechanisms for the patient subgroups. Hypermutated tumors are depleted of immunosuppressive cells and show upregulation of immunoinhibitory molecules. Non-hypermutated tumors are enriched with immunosuppressive cells, and the expression of immunoinhibitors and MHC molecules is downregulated. Reconstruction of the interaction network of tumor-infiltrating lymphocytes and immunomodulatory molecules followed by a validation with 11 independent cohorts (n = 1,945) identifies BCMA as a novel druggable target. Finally, linear regression modeling identifies major determinants of tumor imm...