Molecular Pathways of Colon Inflammation Induced by Cancer Immunotherapy

Cell. 2020 Aug 6;182(3):655-671.e22. doi: 10.1016/j.cell.2020.06.001. Epub 2020 Jun 29.

Abstract

Checkpoint blockade with antibodies specific for the PD-1 and CTLA-4 inhibitory receptors can induce durable responses in a wide range of human cancers. However, the immunological mechanisms responsible for severe inflammatory side effects remain poorly understood. Here we report a comprehensive single-cell analysis of immune cell populations in colitis, a common and severe side effect of checkpoint blockade. We observed a striking accumulation of CD8 T cells with highly cytotoxic and proliferative states and no evidence of regulatory T cell depletion. T cell receptor (TCR) sequence analysis demonstrated that a substantial fraction of colitis-associated CD8 T cells originated from tissue-resident populations, explaining the frequently early onset of colitis symptoms following treatment initiation. Our analysis also identified cytokines, chemokines, and surface receptors that could serve as therapeutic targets for colitis and potentially other inflammatory side effects of checkpoint blockade.

Keywords: CTLA-4; IFNγ; PD-1; TNFα; Trm; cancer; checkpoint blockade; cytotoxic T cells; immune-related adverse events; inflammatory cytokines; irAEs; tissue-resident memory T cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • CTLA-4 Antigen / immunology*
  • CTLA-4 Antigen / metabolism
  • Chemokines / metabolism
  • Colitis / drug therapy
  • Colitis / genetics
  • Colitis / immunology
  • Colitis / metabolism*
  • Cytokines / metabolism
  • Flow Cytometry
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / immunology
  • Humans
  • Immune Checkpoint Inhibitors / adverse effects*
  • Immunotherapy / adverse effects*
  • Inflammation / drug therapy
  • Inflammation / genetics
  • Inflammation / metabolism
  • Melanoma / genetics
  • Melanoma / immunology
  • Melanoma / metabolism
  • Multigene Family
  • Myeloid Cells / cytology
  • Myeloid Cells / metabolism*
  • RNA-Seq
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, CXCR3 / genetics
  • Receptors, CXCR3 / metabolism
  • Receptors, CXCR6 / genetics
  • Receptors, CXCR6 / metabolism
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / metabolism*
  • Single-Cell Analysis
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / metabolism

Substances

  • CTLA-4 Antigen
  • CXCR3 protein, human
  • CXCR6 protein, human
  • Chemokines
  • Cytokines
  • Immune Checkpoint Inhibitors
  • Receptors, Antigen, T-Cell
  • Receptors, CXCR3
  • Receptors, CXCR6
  • Receptors, Chemokine