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

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 HodiGenevieve 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

Research output: Contribution to journalArticlepeer-review

802 Scopus citations

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. Single-cell sequencing of checkpoint-inhibitor-resistant melanomas identifies predictive signatures to guide therapeutic approaches to overcome immunotherapy resistance.

Original languageEnglish
Pages (from-to)984-997.e24
JournalCell
Volume175
Issue number4
DOIs
StatePublished - Nov 1 2018

Keywords

  • Aged
  • Aged, 80 and over
  • Animals
  • Antineoplastic Agents/pharmacology
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 4/antagonists & inhibitors
  • Cyclin-Dependent Kinase 6/antagonists & inhibitors
  • Female
  • Humans
  • Immunotherapy/methods
  • Male
  • Melanoma/drug therapy
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Programmed Cell Death 1 Receptor/antagonists & inhibitors
  • Protein Kinase Inhibitors/pharmacology
  • T-Lymphocytes/immunology
  • Tumor Escape

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