T cell repertoire diversification is associated with immune related toxicities following CTLA-4 blockade in cancer patients

Immune checkpoint inhibitors can induce clinical responses with many cancers but also immune-related adverse events (IRAEs). Mechanisms driving IRAEs are unknown. Because CTLA-4 blockade leads to proliferation of circulating T cells, we examined whether ipilimumab leads to clonal expansion of tissue-reactive T cells. Rather than narrowing the T cell repertoire to a limited number of clones, ipilimumab induced greater repertoire diversification in IRAE patients compared to patients without IRAEs, with increases in the numbers of clonotypes, including newly detected clones, and declines in T cell clonality overall. Initial repertoire broadening occurred within 2 weeks of treatment, preceding IRAEs. IRAE patients demonstrated greater diversity in CD4+ and CD8+ T cells, but no differences in regulatory T cell numbers relative to patients without IRAEs. PSA responses to ipilimumab were also associated with increased T cell diversity. Hence, immune repertoire diversification immediately following checkpoint inhibition can be detrimental and beneficial for cancer patients.

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