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