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

CS Boddupalli, N Bar, K Kadaveru, M Krauthammer… - JCI insight, 2016 - ncbi.nlm.nih.gov
CS Boddupalli, N Bar, K Kadaveru, M Krauthammer, N Pornputtapong, Z Mai, S Ariyan
JCI insight, 2016ncbi.nlm.nih.gov
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 (T RM) 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 …
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 (T RM) 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 T RM 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 T RM 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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