Immunogenic neoantigens derived from gene fusions stimulate T cell responses

Wei Yang, Ken Wing Lee, Raghvendra M. Srivastava, Fengshen Kuo, Chirag Krishna, Diego Chowell, Vladimir Makarov, Douglas Hoen, Martin G. Dalin, Leonard Wexler, Ronald Ghossein, Nora Katabi, Zaineb Nadeem, Marc A. Cohen, S. Ken Tian, Nicolas Robine, Kanika Arora, Heather Geiger, Phaedra Agius, Nancy BouvierKety Huberman, Katelynd Vanness, Jonathan J. Havel, Jennifer S. Sims, Robert M. Samstein, Rajarsi Mandal, Justin Tepe, Ian Ganly, Alan L. Ho, Nadeem Riaz, Richard J. Wong, Neerav Shukla, Timothy A. Chan, Luc G.T. Morris

Research output: Contribution to journalLetter

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.

Original languageEnglish (US)
Pages (from-to)767-775
Number of pages9
JournalNature medicine
Volume25
Issue number5
DOIs
Publication statusPublished - May 1 2019
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Yang, W., Lee, K. W., Srivastava, R. M., Kuo, F., Krishna, C., Chowell, D., ... Morris, L. G. T. (2019). Immunogenic neoantigens derived from gene fusions stimulate T cell responses. Nature medicine, 25(5), 767-775. https://doi.org/10.1038/s41591-019-0434-2