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Tumor heterogeneity and clonal cooperation influence the immune selection of IFN-γ-signaling mutant cancer cells
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Tumor heterogeneity and clonal cooperation influence the immune selection of IFN-γ-signaling mutant cancer cells
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Journal Article
Tumor heterogeneity and clonal cooperation influence the immune selection of IFN-γ-signaling mutant cancer cells
2020
Overview
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.
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
