Molecular Pathways of Colon Inflammation Induced by Cancer Immunotherapy

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 strong enrichment of several T cell clusters in colitis lesions compared to control cases, in particular a striking accumulation of CD8 T cells with signatures reflecting highly cytotoxic and proliferative states. 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. Overall design: Samples from 22 patients from 3 different cohorts (Normal control, +CPI no colitis, +CPI colitis)

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