Tumor heterogeneity and clonal cooperation influence the immune selection of IFN-γ-signaling mutant cancer cells

Jason B. Williams, Shuyin Li, Emily F. Higgs, Alexandra Cabanov, Xiaozhong Wang, Haochu Huang, Thomas F. Gajewski*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

89 Scopus citations

Abstract

PD-1/PD-L1 blockade can promote robust tumor regression yet secondary resistance often occurs as immune selective pressure drives outgrowth of resistant tumor clones. Here using a genome-wide CRISPR screen in B16.SIY melanoma cells, we confirm Ifngr2 and Jak1 as important genes conferring sensitivity to T cell-mediated killing in vitro. However, when implanted into mice, these Ifngr2- and Jak1-deficient tumors paradoxically are better controlled immunologically. This phenotype maps to defective PD-L1 upregulation on mutant tumor cells, which improves anti-tumor efficacy of CD8+ T cells. To reconcile these observations with clinical reports of anti-PD-1 resistance linked to emergence of IFN-γ signaling mutants, we show that when mixed with wild-type tumor cells, IFN-γ-insensitive tumor cells indeed grow out, which depends upon PD-L1 expression by wild-type cells. Our results illustrate the complexity of functions for IFN-γ in anti-tumor immunity and demonstrate that intratumor heterogeneity and clonal cooperation can contribute to immunotherapy resistance.

Original languageEnglish (US)
Article number602
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

Funding

This work was supported by R35CA210098 and a CBC Catalyst Award. J.B.W. was funded by Immunology Training Grant T32 AI07090. The flow cytometry core facility and genomics core facility at the University of Chicago are supported by a Cancer Center Support Grant (P30CA014599). We would like to acknowledge Drs. Maria-Luisa Alegre and Justin Kline for insightful comments about this study, and Yesika Contreras Duarte for her assistance with sample processing and data acquisition.

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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