Immune toxicities elicted by CTLA-4 blockade in cancer patients are associated with early diversification of the T-cell repertoire

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Abstract

While immune checkpoint blockade elicits efficacious responses in many patients with cancer, it also produces a diverse and unpredictable number of immune-related adverse events (IRAE). Mechanisms driving IRAEs are generally unknown. Because CTLA-4 blockade leads to proliferation of circulating T cells, we examined in this study whether ipilimumab treatment 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 diversification in the T-cell repertoire in IRAE patients compared with patients without IRAEs. Specifically, ipilimumab triggered increases in the numbers of clonotypes, including newly detected clones and a decline in overall T-cell clonality. Initial broadening in the repertoire occurred within 2 weeks of treatment, preceding IRAE onset. IRAE patients exhibited greater diversity of CD4+ and CD8+ T cells, but showed no differences in regulatory T-cell numbers relative to patients without IRAEs. Prostatespecific antigen responses to ipilimumab were also associated with increased T-cell diversity. Our results show how rapid diversification in the immune repertoire immediately after checkpoint blockade can be both detrimental and beneficial for patients with cancer.

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Oh, D. Y., Cham, J., Zhang, L., Fong, G., Kwek, S. S., Klinger, M., … Fong, L. (2017). Immune toxicities elicted by CTLA-4 blockade in cancer patients are associated with early diversification of the T-cell repertoire. Cancer Research, 77(6), 1322–1330. https://doi.org/10.1158/0008-5472.CAN-16-2324

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