@article{a81d25368b1e40b9b5e4b72d721b5730,
title = "Immunogenic neoantigens derived from gene fusions stimulate T cell responses",
abstract = "Anti-tumor immunity is driven by self versus non-self discrimination. Many immunotherapeutic approaches to cancer have taken advantage of tumor neoantigens derived from somatic mutations. Here, we demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immunotherapy. We identified an exceptional responder with metastatic head and neck cancer who experienced a complete response to immune checkpoint inhibitor therapy, despite a low mutational load and minimal pre-treatment immune infiltration in the tumor. Using whole-genome sequencing and RNA sequencing, we identified a novel gene fusion and demonstrated that it produces a neoantigen that can specifically elicit a host cytotoxic T cell response. In a cohort of head and neck tumors with low mutation burden, minimal immune infiltration and prevalent gene fusions, we also identified gene fusion-derived neoantigens that generate cytotoxic T cell responses. Finally, analyzing additional datasets of fusion-positive cancers, including checkpoint-inhibitor-treated tumors, we found evidence of immune surveillance resulting in negative selective pressure against gene fusion-derived neoantigens. These findings highlight an important class of tumor-specific antigens and have implications for targeting gene fusion events in cancers that would otherwise be less poised for response to immunotherapy, including cancers with low mutational load and minimal immune infiltration.",
author = "Wei Yang and Lee, {Ken Wing} and Srivastava, {Raghvendra M.} and Fengshen Kuo and Chirag Krishna and Diego Chowell and Vladimir Makarov and Douglas Hoen and Dalin, {Martin G.} and Leonard Wexler and Ronald Ghossein and Nora Katabi and Zaineb Nadeem and Cohen, {Marc A.} and Tian, {S. Ken} and Nicolas Robine and Kanika Arora and Heather Geiger and Phaedra Agius and Nancy Bouvier and Kety Huberman and Katelynd Vanness and Havel, {Jonathan J.} and Sims, {Jennifer S.} and Samstein, {Robert M.} and Rajarsi Mandal and Justin Tepe and Ian Ganly and Ho, {Alan L.} and Nadeem Riaz and Wong, {Richard J.} and Neerav Shukla and Chan, {Timothy A.} and Morris, {Luc G.T.}",
note = "Funding Information: The authors wish to acknowledge our patients and their families who selflessly contributed time and samples to support this research, the patients and investigators who contributed to the TCGA studies analyzed here, McKenzy and Beth Hupke, members of the Timothy Chan Laboratory for insightful discussions, members of the MSKCC Immunogenomics and Precision Oncology Platform and the Molecular Cytology Core Facility of MSKCC. This work was supported by the NIH/NCI Cancer Center Support Grant no. P30 CA008748 (to MSKCC), Cycle for Survival (R.J.W., L.G.T.M. and T.A.C.), the Frederick Adler Chair at MSKCC, the Jayme Flowers Fund, the Sebastian Nativo Fund, the Damon Runyon Cancer Research Foundation, NIH grant nos. K08 DE024774 and NIH R01 DE027738 (L.G.T.M.), the Adenoid Cystic Carcinoma Cancer Research Foundation, (T.A.C., A.L.H. and L.G.T.M.), The Geoffrey Beene Junior Faculty Chair (A.L.H.), NIH grant nos. R01 CA205426 and NIH R35 CA232097, the Pershing Square Sohn Cancer Research Alliance, the STARR Cancer Consortium and the PaineWebber Chair at MSKCC (T.A.C.). Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2019",
month = may,
day = "1",
doi = "10.1038/s41591-019-0434-2",
language = "English (US)",
volume = "25",
pages = "767--775",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "5",
}