期刊
NATURE MEDICINE
卷 25, 期 5, 页码 767-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41591-019-0434-2
关键词
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资金
- NIH/NCI Cancer Center Support Grant [P30 CA008748]
- Cycle for Survival
- Frederick Adler Chair at MSKCC
- Jayme Flowers Fund
- Damon Runyon Cancer Research Foundation
- NIH [K08 DE024774, R01 DE027738, R01 CA205426, R35 CA232097]
- Adenoid Cystic Carcinoma Cancer Research Foundation
- Geoffrey Beene Junior Faculty Chair
- Pershing Square Sohn Cancer Research Alliance
- STARR Cancer Consortium
- PaineWebber Chair at MSKCC
- Sebastian Nativo Fund
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.
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