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Interlesional diversity of T cell receptors in melanoma with immune checkpoints enriched in tissue-resident memory T cells
Chandra Sekhar Boddupalli, … , Madhav V. Dhodapkar, Kavita M. Dhodapkar
Chandra Sekhar Boddupalli, … , Madhav V. Dhodapkar, Kavita M. Dhodapkar
Published December 22, 2016
Citation Information: JCI Insight. 2016;1(21):e88955. https://doi.org/10.1172/jci.insight.88955.
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Research Article Oncology

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

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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.

Authors

Chandra Sekhar Boddupalli, Noffar Bar, Krishna Kadaveru, Michael Krauthammer, Natopol Pornputtapong, Zifeng Mai, Stephan Ariyan, Deepak Narayan, Harriet Kluger, Yanhong Deng, Rakesh Verma, Rituparna Das, Antonella Bacchiocchi, Ruth Halaban, Mario Sznol, Madhav V. Dhodapkar, Kavita M. Dhodapkar

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Figure 1

Melanoma tissue is enriched for memory T cells expressing higher levels of inhibitory checkpoints compared with T cells in peripheral blood.

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Melanoma tissue is enriched for memory T cells expressing higher levels ...
Paired blood and tumor tissue (n = 10) were stained and analyzed together using single-cell mass cytometry. Data were acquired using a CyTOF2 machine and analyzed using the CyTOBank analysis software, including the viSNE analysis. (A) viSNE analysis of the CD3+ T cells in the blood and tumor of a representative patient. Expression of CD4/CD8/CCR7 and CD45RO is shown. (B) viSNE analysis of CD3+ T cells in paired blood and tumor tissue showing expression of immune checkpoint proteins PD-1, TIM3, BTLA, and PD-L1. Data are from a representative patient. (C) The expression of immune checkpoints on CD3, CD4, and CD8 T cells in paired blood and tumor tissue samples (n = 10). *P < 0.01 (paired t test followed by multiple test correction using Hochberg sequential test).

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