Immune Toxicities Elicted by CTLA-4 Blockade in Cancer Patients Are Associated with Early Diversification of the T-cell Repertoire

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 6; pp. 1322 - 1330
• Main Authors: Oh, David Y, Cham, Jason, Zhang, Li, Fong, Grant, Kwek, Serena S, Klinger, Mark, Faham, Malek, Fong, Lawrence
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 15-03-2017
• Subjects: Antibodies, Monoclonal - pharmacology; Cancer; CD4 antigen; CD8 antigen; Cell proliferation; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 protein; Diversification; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Humans; Immune checkpoint inhibitors; Ipilimumab; Lymphocytes; Lymphocytes T; Male; Monoclonal antibodies; Prognosis; Prostate; Prostate-specific antigen; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - immunology; Prostatic Neoplasms, Castration-Resistant - pathology; T cell receptors; T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Toxicity
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-16-2324

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. Prostate-specific 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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