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JCI Insight. 2016 Dec 22;1(21):e88955. doi: 10.1172/jci.insight.88955.

Interlesional diversity of T cell receptors in melanoma with immune checkpoints enriched in tissue-resident memory T cells.

Author information

1
Department of Medicine.
2
Department of Pediatrics.
3
Program for Computational Biology and Bioinformatics,; Department of Pathology.
4
Department of Pathology.
5
Department of Surgery.
6
Department of Medicine,; Yale Cancer Center.
7
Yale Center for Analytic Sciences.
8
Department of Dermatology.
9
Department of Medicine,; Yale Cancer Center,; Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
10
Department of Pediatrics,; Yale Cancer Center.

Abstract

Heterogeneity of tumor cells and their microenvironment can affect outcome in cancer. Blockade of immune checkpoints (ICPs) expressed only on a subset of immune cells leads to durable responses in advanced melanoma. Tissue-resident memory T (TRM) cells have recently emerged as a distinct subset of memory T cells in nonlymphoid tissues. Here, we show that functional properties and expression of ICPs within tumor-infiltrating lymphocytes (TILs) differ from those of blood T cells. TILs secrete less IL-2, IFN-γ, and TNF-α compared with circulating counterparts, and expression of VEGF correlated with reduced TIL infiltration. Within tumors, ICPs are particularly enriched within T cells with phenotype and genomic features of TRM cells and the CD16+ subset of myeloid cells. Concurrent T cell receptor (TCR) and tumor exome sequencing of individual metastases in the same patient revealed that interlesional diversity of TCRs exceeded differences in mutation/neoantigen load in tumor cells. These findings suggest that the TRM subset of TILs may be the major target of ICP blockade and illustrate interlesional diversity of tissue-resident TCRs within individual metastases, which did not equilibrate between metastases and may differentially affect the outcome of immune therapy at each site.

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