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Cell DOI:10.1016/j.cell.2018.09.006

A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade.

Publication TypeJournal Article
Year of Publication2018
AuthorsJerby-Arnon, L, Shah, P, Cuoco, MS, Rodman, C, Su, M-J, Melms, JC, Leeson, R, Kanodia, A, Mei, S, Lin, J-R, Wang, S, Rabasha, B, Liu, D, Zhang, G, Margolais, C, Ashenberg, O, Ott, PA, Buchbinder, EI, Haq, R, F Hodi, S, Boland, GM, Sullivan, RJ, Frederick, DT, Miao, B, Moll, T, Flaherty, KT, Herlyn, M, Jenkins, RW, Thummalapalli, R, Kowalczyk, MS, Cañadas, I, Schilling, B, Cartwright, ANR, Luoma, AM, Malu, S, Hwu, P, Bernatchez, C, Forget, M-A, Barbie, DA, Shalek, AK, Tirosh, I, Sorger, PK, Wucherpfennig, K, Van Allen, EM, Schadendorf, D, Johnson, BE, Rotem, A, Rozenblatt-Rosen, O, Garraway, LA, Yoon, CH, Izar, B, Regev, A
Date Published2018 Nov 01
KeywordsAged, Aged, 80 and over, Animals, Antineoplastic Agents, Cell Line, Tumor, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Female, Humans, Immunotherapy, Male, Melanoma, Mice, Mice, Inbred C57BL, Middle Aged, Programmed Cell Death 1 Receptor, Protein Kinase Inhibitors, T-Lymphocytes, Tumor Escape

Immune checkpoint inhibitors (ICIs) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the molecular underpinnings of such resistance remain elusive. Here, we leveraged single-cell RNA sequencing (scRNA-seq) from 33 melanoma tumors and computational analyses to interrogate malignant cell states that promote immune evasion. We identified a resistance program expressed by malignant cells that is associated with T cell exclusion and immune evasion. The program is expressed prior to immunotherapy, characterizes cold niches in situ, and predicts clinical responses to anti-PD-1 therapy in an independent cohort of 112 melanoma patients. CDK4/6-inhibition represses this program in individual malignant cells, induces senescence, and reduces melanoma tumor outgrowth in mouse models in vivo when given in combination with immunotherapy. Our study provides a high-resolution landscape of ICI-resistant cell states, identifies clinically predictive signatures, and suggests new therapeutic strategies to overcome immunotherapy resistance.


Alternate JournalCell
PubMed ID30388455
PubMed Central IDPMC6410377
Grant ListU24 CA180922 / CA / NCI NIH HHS / United States
R01 CA173750 / CA / NCI NIH HHS / United States
P30 CA010815 / CA / NCI NIH HHS / United States
K08 CA222663 / CA / NCI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
P30 CA014051 / CA / NCI NIH HHS / United States
R33 CA202820 / CA / NCI NIH HHS / United States
T32 CA207021 / CA / NCI NIH HHS / United States