Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-14290-4
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Funding
- CBC Catalyst Award
- Immunology Training Grant [T32 AI07090]
- Cancer Center Support Grant [P30CA014599]
- [R35CA210098]
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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-gamma signaling mutants, we show that when mixed with wild-type tumor cells, IFN-gamma -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-gamma in anti-tumor immunity and demonstrate that intratumor heterogeneity and clonal cooperation can contribute to immunotherapy resistance. Melanoma is a cancer that responds relatively well to immunotherapy but resistance does ensue. Here, the authors show that loss of IFNGR2 or JAK1 in a melanoma cell line enhances T cell mediated lysis, however these cells are paradoxically more sensitive to immune-mediated tumor control in vivo due to the loss of PD-L1.
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