@article{43508d23404e4127b769e2998e8ba937,
title = "A dormant TIL phenotype defines non-small cell lung carcinomas sensitive to immune checkpoint blockers",
abstract = "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.",
author = "Gettinger, {S. N.} and J. Choi and N. Mani and Sanmamed, {M. F.} and I. Datar and Ryan Sowell and Du, {Victor Y.} and E. Kaftan and S. Goldberg and W. Dong and D. Zelterman and K. Politi and P. Kavathas and S. Kaech and X. Yu and H. Zhao and J. Schlessinger and R. Lifton and Rimm, {D. L.} and L. Chen and Herbst, {R. S.} and Schalper, {K. A.}",
note = "Funding Information: Competing interests: In the last 12 months Dr. Kurt Schalper has been speaker or consultant for Merck, Takeda Pharmaceuticals, Shattuck Labs and Celgene. His laboratory has received research funding from Vasculox/Tioma, Navigate Biopharma, Tesaro Inc, Onkaido Therapeutics/Moderna, Takeda Pharmaceuticals and Surface Oncology. Dr. David Rimm is consultant or advisor to AstraZeneca, Agendia, Agilent, Biocept, Bristo-Myers-Squibb, Cell Signaling Technology. Cepheid, Merck, Optrascan, Perkinelmer and Ultivue. His laboratory has received research funding from AstraZeneca, Cepheid, Navigate/Novartis, NextCure, Gilead Sciences, Ultivue and Perkinelmer. Dr. Rimm also holds equity in PixelGear. Dr. Katerina Politi serves as consultant or advisor for AstraZeneca, Merck, Novartis and Tocagen. Her laboratory received research funds from AstraZeneca, Roche, Kolltan and Symphogen. Dr. Politi also holds royalties in IP licenced from Memorial Sloan Kettering Cancer Center to Molecular MD. Dr. Sarah Goldberg serves as consultant or advisor for AstraZeneca, Bristol-Myers Squibb, Lilly and Boehringer Ingelheim. She received research support from AstraZeneca. Lieping Chen serves as consultant or advisor for Pfizer, Vcanbio and GenomiCare. He is a scientific founder of NextCure and Tayu Biotech. His laboratory receives research funding from NextCure. The remaining authors declare no competing interests. with the content of this work. Funding Information: This work was funded by the Yale SPORE in Lung Cancer P50CA196530 (to R.S.H.), a Yale SPORE in Lung Cancer Career Development Program award (to K.A.S.) and Developmental Project (to P.B.K. and S.K.), a Department of Defense Lung Cancer Research Program Career Development Award #LC150383 (to KAS), Stand Up To Cancer - American Cancer Society Lung Cancer Dream Team Translational Research Grant SU2C-AACR-DT17-15; a Lung Cancer Research Foundation grant (to K.A.S.), project NIH R01CA195720 (to K.P. and S.K.), the Melissa Marottoli Hogan Foundation, Diane and David B. Heller Charitable Foundation and the Yale-Gilead Sciences Research collaboration. MFS is recipient of SITC-Astra Zeneca Cancer Immunotherapy Clinical Fellowship in Non-small cell lung cancer (NSCLC). We thank Nolan Maloney for performing the peptide binding assay. Publisher Copyright: {\textcopyright} 2018, The Author(s).",
year = "2018",
month = dec,
day = "1",
doi = "10.1038/s41467-018-05032-8",
language = "English",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}