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 and Thomas F. Gajewski ()
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Jason B. Williams: The University of Chicago
Shuyin Li: The University of Chicago
Emily F. Higgs: The University of Chicago
Alexandra Cabanov: The University of Chicago
Xiaozhong Wang: Northwestern University
Haochu Huang: The University of Chicago
Thomas F. Gajewski: The University of Chicago

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14290-4

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