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

doi:10.1038/s41467-020-14290-4

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

Molecular Biosciences

Research output: Contribution to journal › Article › peer-review

59 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 language	English (US)
Article number	602
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-14290-4
State	Published - Dec 1 2020

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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

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.",

author = "Williams, {Jason B.} and Shuyin Li and Higgs, {Emily F.} and Alexandra Cabanov and Xiaozhong Wang and Haochu Huang and Gajewski, {Thomas F.}",

note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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AU - Huang, Haochu

AU - Gajewski, Thomas F.

N1 - Funding Information: 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. Publisher Copyright: © 2020, The Author(s).

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N2 - 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.

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

Abstract

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