Immunity
Volume 55, Issue 4, 12 April 2022, Pages 671-685.e10
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Article
The interferon-stimulated gene RIPK1 regulates cancer cell intrinsic and extrinsic resistance to immune checkpoint blockade

https://doi.org/10.1016/j.immuni.2022.03.007Get rights and content
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Highlights

  • Cancer cell RIPK1 controls IFN-γ-driven immune checkpoint blockade (ICB) resistance

  • Tumors with RIPK1 resist immune cell killing and secrete suppressive cytokines

  • Deleting RIPK1 decreases ARG1+ macrophages, promotes TNF killing, and improves ICB

  • RIPK1-mediated ICB resistance requires scaffolding but not kinase function

Summary

Interferon-gamma (IFN-γ) 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-κB 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.

Data and code availability

  • Single-cell RNA sequencing data have been deposited at the GEO and are publicly available as of the date of publication. Accession numbers are listed in the Key Resources table.

  • This manuscript analyzes existing, publicly available data. These accession numbers for the datasets are listed in the Key Resources table.

  • This paper does not report original code.

  • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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