@article{be0ab5d2b19b40b3977150e9a44f9aa6,
title = "Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma",
abstract = "Treatment of cancer has been revolutionized by immune checkpoint blockade therapies. Despite the high rate of response in advanced melanoma, the majority of patients succumb to disease. To identify factors associated with success or failure of checkpoint therapy, we profiled transcriptomes of 16,291 individual immune cells from 48 tumor samples of melanoma patients treated with checkpoint inhibitors. Two distinct states of CD8+ T cells were defined by clustering and associated with patient tumor regression or progression. A single transcription factor, TCF7, was visualized within CD8+ T cells in fixed tumor samples and predicted positive clinical outcome in an independent cohort of checkpoint-treated patients. We delineated the epigenetic landscape and clonality of these T cell states and demonstrated enhanced antitumor immunity by targeting novel combinations of factors in exhausted cells. Our study of immune cell transcriptomes from tumors demonstrates a strategy for identifying predictors, mechanisms, and targets for enhancing checkpoint immunotherapy. Single-cell analysis of immune cells from melanoma patients treated with immune checkpoint therapy uncovers a TCF7+ memory-like state in the cytotoxic T cell population and demonstrates its association with a positive outcome.",
keywords = "CD8 T cells, TCF7, cancer immunotherapy, checkpoint blockade, single-cell RNA-seq",
author = "Moshe Sade-Feldman and Keren Yizhak and Bjorgaard, {Stacey L.} and Ray, {John P.} and {de Boer}, {Carl G.} and Jenkins, {Russell W.} and Lieb, {David J.} and Chen, {Jonathan H.} and Frederick, {Dennie T.} and Michal Barzily-Rokni and Freeman, {Samuel S.} and Alexandre Reuben and Hoover, {Paul J.} and Villani, {Alexandra Chlo{\'e}} and Elena Ivanova and Andrew Portell and Lizotte, {Patrick H.} and Aref, {Amir R.} and Eliane, {Jean Pierre} and Hammond, {Marc R.} and Hans Vitzthum and Blackmon, {Shauna M.} and Bo Li and Vancheswaran Gopalakrishnan and Reddy, {Sangeetha M.} and Cooper, {Zachary A.} and Paweletz, {Cloud P.} and Barbie, {David A.} and Anat Stemmer-Rachamimov and Flaherty, {Keith T.} and Wargo, {Jennifer A.} and Boland, {Genevieve M.} and Sullivan, {Ryan J.} and Gad Getz and Nir Hacohen",
note = "Funding Information: We thank the Genomics Platform of the Broad Institute of Harvard and MIT for the whole-exome sequencing performed in this study. All cytometric findings reported here were performed in the MGH Department of Pathology Flow and Image Cytometry Research Core, which obtained support from the NIH Shared Instrumentation program with grants 1S10OD012027-01A1, 1S10OD016372-01, 1S10RR020936-01, and 1S10RR023440-01A1. Additional thanks to Natasha Mathur of the Belfer Center for applied Cancer Sciences for assistance with immunofluorescence staining. The research was supported by grants from Broad Next-10 (N.H.), Cancer Research Institute (Clinic and Laboratory Integration Program, N.H.), Adelson Medical Research Foundation (N.H), Sanofi (N.H.), the David P. Ryan, MD, Chair funded by a gift from Arthur, Sandra, and Sarah Irving (N.H.), the Paul C. Zamecnick, MD, Chair in Oncology at MGH (G.G.), NIH/NHGRI (5U54HG003067, PIs: Stacey Gabriel and Eric S. Lander), NIH/NCI (R01CA208756, PI: N.H.; U54CA224068, PIs: Ryan Corcoran and K.T.F.). We also thank the following grants for their support: Institute for Medical Research Israel-Canada (M.S.-F.), Tosteson & Fund for Medical Discovery fellowships (M.S.-F.), the Broad-ISF fellowship (K.Y.) Weizmann award for Women in Science (K.Y.), NIH award number F32AI129249 (J.P.R.), 1T32CA207021-01 (J.H.C.), Robert A. and Renee E. Belfer (R.W.J.), John R. Svenson Fellowship (R.W.J.), NCI-R01 CA190394-01 (D.A.B.), NCI-U01 CA214381 (D.A.B., R.W.J.), and the Expect Miracles Foundation (C.P.P.). Funding Information: Parts of the study have been submitted as a patent application. N.H. is on the SAB, owns shares in Neon Therapeutics, and consults for IFM Therapeutics. G.G. is receiving research funds from IBM and Pharmacyclics and is an inventor on multiple patent applications, including one related to MuTect. R.W.J. and D.A.B are inventors on pending patent 15/540,346 and PCT/US2016/012450. R.W.J. is a consultant for Apricity Health, LLC. D.A.B. is a consultant for N of One. C.P.P. is on the SAB of DropWorks and received honoraria from AstraZeneca, Biorad. Z.A.C. is an employee of MedImmune. A.S.-R. consults for Recombinetics and Novartis. J.A.W. is a paid speaker for Imedex, Dava Oncology, Omniprex, Illumina, Gilead, MedImmune, and Bristol Meyers Squibb; is a consultant/SAB member for Roche-Genentech, Novartis, Astra-Zeneca, Glaxo Smith Klein, Bristol Meyers Squibb, and Merck; and receives clinical trial support from Glaxo Smith Klein, Roche-Genentech, Bristol Meyers Squibb, and Novartis. V.G. and J.A.W. are inventors on USPTO patent (PCT/US17/53.717) and report consultancy fees from MicrobiomeDX and ExpertConnect. G.M.B. has a sponsored research agreement with Takeda Oncology. K.T.F. owns equity in Shattuck Labs, Checkmate, X4 Pharmaceuticals; is a consultant/advisory board member for Novartis, Genentech, BMS, Merck, Takeda, Verastem, Checkmate, X4 Pharmaceuticals, Sanofi, Amgen, Incyte, Adaptimmune, Shattuck Labs, Arch Oncology, and Apricity; and receives research support from Novartis, Genentech, Sanofi, and Amgen. R.J.S. is a paid speaker for Array, Novartis, and Genentech; is a paid consultant/advisory board member for Amgen, Array, Novartis, Merck, Compugen, and Syndax; and has received research funding from Amgen and Merck. Funding Information: We thank the Genomics Platform of the Broad Institute of Harvard and MIT for the whole-exome sequencing performed in this study. All cytometric findings reported here were performed in the MGH Department of Pathology Flow and Image Cytometry Research Core, which obtained support from the NIH Shared Instrumentation program with grants 1S10OD012027-01A1 , 1S10OD016372-01 , 1S10RR020936-01 , and 1S10RR023440-01A1 . Additional thanks to Natasha Mathur of the Belfer Center for applied Cancer Sciences for assistance with immunofluorescence staining. The research was supported by grants from Broad Next-10 (N.H.), Cancer Research Institute (Clinic and Laboratory Integration Program, N.H.), Adelson Medical Research Foundation (N.H), Sanofi (N.H.), the David P. Ryan, MD, Chair funded by a gift from Arthur, Sandra, and Sarah Irving (N.H.), the Paul C. Zamecnick, MD, Chair in Oncology at MGH (G.G.), NIH/NHGRI ( 5U54HG003067 , PIs: Stacey Gabriel and Eric S. Lander), NIH/NCI ( R01CA208756 , PI: N.H.; U54CA224068 , PIs: Ryan Corcoran and K.T.F.). We also thank the following grants for their support: Institute for Medical Research Israel-Canada (M.S.-F.), Tosteson & Fund for Medical Discovery fellowships (M.S.-F.), the Broad-ISF fellowship (K.Y.) Weizmann award for Women in Science (K.Y.), NIH award number F32AI129249 (J.P.R.), 1T32CA207021-01 (J.H.C.), Robert A. and Renee E. Belfer (R.W.J.), John R. Svenson Fellowship (R.W.J.), NCI-R01 CA190394-01 (D.A.B.), NCI-U01 CA214381 (D.A.B., R.W.J.), and the Expect Miracles Foundation (C.P.P.). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = nov,
day = "1",
doi = "10.1016/j.cell.2018.10.038",
language = "English (US)",
volume = "175",
pages = "998--1013.e20",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",
}