The interferon-stimulated gene RIPK1 regulates cancer cell intrinsic and extrinsic resistance to immune checkpoint blockade

Immunity. 2022 Apr 12;55(4):671-685.e10. doi: 10.1016/j.immuni.2022.03.007.

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+ 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.

MeSH terms

  • Animals
  • Drug Resistance, Neoplasm*
  • Immune Checkpoint Inhibitors*
  • Immunotherapy
  • Interferon-gamma / metabolism
  • Interferons* / metabolism
  • Mice
  • NF-kappa B / metabolism
  • Neoplasms* / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases* / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases* / metabolism

Substances

  • Immune Checkpoint Inhibitors
  • NF-kappa B
  • Interferon-gamma
  • Interferons
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse