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Cell DOI:10.1016/j.cell.2018.10.038

Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma.

Publication TypeJournal Article
Year of Publication2018
AuthorsSade-Feldman, M, Yizhak, K, Bjorgaard, SL, Ray, JP, de Boer, CG, Jenkins, RW, Lieb, DJ, Chen, JH, Frederick, DT, Barzily-Rokni, M, Freeman, SS, Reuben, A, Hoover, PJ, Villani, A-C, Ivanova, E, Portell, A, Lizotte, PH, Aref, AR, Eliane, J-P, Hammond, MR, Vitzthum, H, Blackmon, SM, Li, B, Gopalakrishnan, V, Reddy, SM, Cooper, ZA, Paweletz, CP, Barbie, DA, Stemmer-Rachamimov, A, Flaherty, KT, Wargo, JA, Boland, GM, Sullivan, RJ, Getz, G, Hacohen, N
Date Published2018 Nov 01
KeywordsAnimals, Antibodies, Monoclonal, Humanized, Antigens, CD, Antineoplastic Agents, Immunological, Apyrase, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Humans, Immunotherapy, Leukocyte Common Antigens, Melanoma, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, T Cell Transcription Factor 1, Transcriptome

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.


Alternate JournalCell
PubMed ID30388456
PubMed Central IDPMC6641984
Grant ListU54 HG003067 / HG / NHGRI NIH HHS / United States
S10 OD016372 / OD / NIH HHS / United States
U01 CA214381 / CA / NCI NIH HHS / United States
S10 OD012027 / OD / NIH HHS / United States
U54 CA224068 / CA / NCI NIH HHS / United States
S10 RR023440 / RR / NCRR NIH HHS / United States
T32 CA207021 / CA / NCI NIH HHS / United States
R01 CA208756 / CA / NCI NIH HHS / United States
F32 AI129249 / AI / NIAID NIH HHS / United States
R01 CA190394 / CA / NCI NIH HHS / United States
S10 RR020936 / RR / NCRR NIH HHS / United States