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 | |
| State | Published - 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
