Molecular Pathways of Colon Inflammation Induced by Cancer Immunotherapy

Adrienne M Luoma; Shengbao Suo; Hannah L Williams; Tatyana Sharova; Keri Sullivan; Michael Manos; Peter Bowling; F Stephen Hodi; Osama Rahma; Ryan J Sullivan; Genevieve M Boland; Jonathan A Nowak; Stephanie K Dougan; Michael Dougan; Guo-Cheng Yuan; Kai W Wucherpfennig

doi:10.1016/j.cell.2020.06.001

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.

Authors

Adrienne M Luoma¹, Shengbao Suo², Hannah L Williams³, Tatyana Sharova⁴, Keri Sullivan⁵, Michael Manos⁶, Peter Bowling⁶, F Stephen Hodi⁶, Osama Rahma⁷, Ryan J Sullivan⁸, Genevieve M Boland⁴, Jonathan A Nowak⁹, Stephanie K Dougan¹, Michael Dougan¹⁰, Guo-Cheng Yuan², Kai W Wucherpfennig¹¹

Affiliations

¹ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
² Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA 02215, USA.
⁴ Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Division of Gastroenterology and Department of Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02114, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA 02215, USA; Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA 02215, USA; Brigham and Women's Hospital and Dana-Farber/Harvard Cancer Center, Boston, MA, USA.
⁸ Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
⁹ Department of Pathology, Brigham & Women's Hospital, Boston, MA 02115, USA.
¹⁰ Division of Gastroenterology and Department of Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02114, USA. Electronic address: mldougan@partners.org.
¹¹ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA; Department of Neurology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: kai_wucherpfennig@dfci.harvard.edu.

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding