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

Jerby-Arnon, Livnat and Shah, Parin and Cuoco, Michael S and Rodman, Christopher and Su, Mei-Ju and Melms, Johannes C and Leeson, Rachel and Kanodia, Abhay and Mei, Shaolin and Lin, Jia-Ren and Wang, Shu and Rabasha, Bokang and Liu, David and Zhang, Gao and Margolais, Claire and Ashenberg, Orr and Ott, Patrick A and Buchbinder, Elizabeth I and Haq, Rizwan and Hodi, F Stephen and Boland, Genevieve M and Sullivan, Ryan J and Frederick, Dennie T and Miao, Benchun and Moll, Tabea and Flaherty, Keith T and Herlyn, Meenhard and Jenkins, Russell W and Thummalapalli, Rohit and Kowalczyk, Monika S and Cañadas, Israel and Schilling, Bastian and Cartwright, Adam N R and Luoma, Adrienne M and Malu, Shruti and Hwu, Patrick and Bernatchez, Chantale and Forget, Marie-Andrée and Barbie, David A and Shalek, Alex K and Tirosh, Itay and Sorger, Peter K and Wucherpfennig, Kai and Van Allen, Eliezer M and Schadendorf, Dirk and Johnson, Bruce E and Rotem, Asaf and Rozenblatt-Rosen, Orit and Garraway, Levi A and Yoon, Charles H and Izar, Benjamin and Regev, Aviv (2018) A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade. Cell, 175 (4). 984-997.e24. ISSN 1097-4172

Abstract

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.

Item Type: Article
Date Deposited: 30 Nov 2018 00:45
Last Modified: 30 Nov 2018 00:45
URI: https://oak.novartis.com/id/eprint/38426

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