期刊
IMMUNITY
卷 55, 期 4, 页码 671-+出版社
CELL PRESS
DOI: 10.1016/j.immuni.2022.03.007
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类别
资金
- Breast Cancer Research Foundation
- Mark Foundation for Cancer Research
- Parker Institute for Cancer Immunotherapy
- NIH [1P01CA210944-01]
Interferon-gamma has various effects on cancer immune checkpoint blockade, including its role in resistance. The study found that the expression of Ripk1 gene is strongly associated with interferon-mediated resistance. RIPK1 diverts TNF signaling in cancer cells, leading to the production of immunosuppressive chemokines and decreased expression of TNF superfamily ligands in T and NK cells.
Interferon-gamma (IFN-gamma) has pleiotropic effects on cancer immune checkpoint blockade (ICB), including roles in ICB resistance. We analyzed gene expression in ICB-sensitive versus ICB-resistant tumor cells and identified a strong association between interferon-mediated resistance and expression of Ripk1, a regulator of tumor necrosis factor (TNF) superfamily receptors. Genetic interaction screening revealed that in cancer cells, RIPK1 diverted TNF signaling through NF-kappa B and away from its role in cell death. This promoted an immunosuppressive chemokine program by cancer cells, enhanced cancer cell survival, and decreased infiltration of T and NK cells expressing TNF superfamily ligands. Deletion of RIPK1 in cancer cells compromised chemokine secretion, decreased ARG1(+) suppressive myeloid cells linked to ICB failure in mice and humans, and improved ICB response driven by CASP8-killing and dependent on T and NK cells. RIPK1-mediated resistance required its ubiquitin scaffolding but not kinase function. Thus, cancer cells co-opt RIPK1 to promote cell-intrinsic and cell-extrinsic resistance to immunotherapy.
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