Changing of the guard

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Science Immunology  06 Sep 2019:
Vol. 4, Issue 39, eaaz2438
DOI: 10.1126/sciimmunol.aaz2438


Anti-PD-1 therapy induces clonal expansion of tumor-specific T cells with antigen specificities distinct from the tumor-specific T cells present before therapy.

Basal cell carcinomas (BCC) are the most common cancers in humans. Most are cured by surgical removal, but rare BCC metastasize and some cannot be fully removed surgically. BCC have high mutational loads and immune checkpoint inhibitors have shown promise in some patients. In this study, the authors used single-cell RNA, TCR, and whole-exome sequencing to study advanced BCC tumors from 11 patients before and after PD-1 inhibitor therapy. PD-1 blockade induced increased T cell infiltration and mutational loss, suggesting immunoediting of tumors. Before treatment, tumors contained clonally expanded populations of CD8+ T cells with markers of tumor specificity. PD-1 blockade increased T follicular helper cells and CD8+ T cells co-expressing markers of chronic T cell activation, exhaustion and tumor specificity. However, these expanded CD8+ T cell clones were most often new clonotypes and not derived from the preexisting pool of tumor infiltrating lymphocytes. 12% of these new clonotypes were found in the blood before treatment, and 26% were detectable in blood after therapy. Similar studies in cutaneous squamous cell carcinomas also demonstrated new clonotypes in the tumor after PD-1 blockade. These studies show that PD-1 blockade can induce the formation and/or recruitment of novel tumor-specific T cells in addition to its known ability to reinvigorate exhausted T cells in the tumor microenvironment.

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