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The interferon-stimulated gene RIPK1 regulates cancer cell intrinsic and extrinsic resistance to immune checkpoint blockade.
- Source :
-
Immunity [Immunity] 2022 Apr 12; Vol. 55 (4), pp. 671-685.e10. - Publication Year :
- 2022
-
Abstract
- 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 <superscript>+</superscript> 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.<br />Competing Interests: Declaration of interests A.J.M. has received research funding from Merck. He is a scientific advisor for Takeda, H3Biomedicine, Xilio, and Related Sciences. A.J.M. is an inventor on patents related to the IFN pathway and an inventor on a filed patent related to modified CAR T cells. A.J.M. is a scientific founder for Dispatch Biotherapeutics.<br /> (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Immunotherapy
Interferon-gamma metabolism
Mice
NF-kappa B metabolism
Drug Resistance, Neoplasm
Immune Checkpoint Inhibitors
Interferons metabolism
Neoplasms genetics
Receptor-Interacting Protein Serine-Threonine Kinases genetics
Receptor-Interacting Protein Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4180
- Volume :
- 55
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Immunity
- Publication Type :
- Academic Journal
- Accession number :
- 35417675
- Full Text :
- https://doi.org/10.1016/j.immuni.2022.03.007