期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-05032-8
关键词
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资金
- Yale SPORE in Lung Cancer [P50CA196530]
- Yale SPORE in Lung Cancer Career Development Program award
- Department of Defense Lung Cancer Research Program [LC150383]
- Stand Up To Cancer - American Cancer Society Lung Cancer Dream Team Translational Research Grant [SU2C-AACR-DT17-15]
- Lung Cancer Research Foundation
- NIH [R01CA195720]
- Melissa Marottoli Hogan Foundation
- Diane and David B. Heller Charitable Foundation
- Yale-Gilead Sciences
- SITC-Astra Zeneca Cancer Immunotherapy Clinical Fellowship in Non-small cell lung cancer (NSCLC)
- NATIONAL CANCER INSTITUTE [P30CA016359, P50CA196530] Funding Source: NIH RePORTER
The biological determinants of sensitivity and resistance to immune checkpoint blockers are not completely understood. To elucidate the role of intratumoral T-cells and their association with the tumor genomic landscape, we perform paired whole exome DNA sequencing and multiplexed quantitative immunofluorescence (QIF) in pre-treatment samples from non-small cell lung carcinoma (NSCLC) patients treated with PD-1 axis blockers. QIF is used to simultaneously measure the level of CD3+ tumor infiltrating lymphocytes (TILs), in situ T-cell proliferation (Ki-67 in CD3) and effector capacity (Granzyme-B in CD3). Elevated mutational load, candidate class-I neoantigens or intratumoral CD3 signal are significantly associated with favorable response to therapy. Additionally, a dormant TIL signature is associated with survival benefit in patients treated with immune checkpoint blockers characterized by elevated TILs with low activation and proliferation. We further demonstrate that dormant TILs can be reinvigorated upon PD-1 blockade in a patient-derived xenograft model.
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