title: Interlesional diversity of T cell receptors in melanoma with immune checkpoints enriched in tissue-resident memory T cells.
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 TRMcells 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 TRMsubset 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.affiliation: Department of Medicine.
authors.forename: Chandra Sekhar
authors.initials: CS
authors.lastname: Boddupalli
authors.affiliation: Department of Medicine.
authors.forename: Noffar
authors.initials: N
authors.lastname: Bar
authors.affiliation: Department of Pediatrics.
authors.forename: Krishna
authors.initials: K
authors.lastname: Kadaveru
authors.affiliation: Program for Computational Biology and Bioinformatics.|Department of Pathology.
authors.forename: Michael
authors.initials: M
authors.lastname: Krauthammer
authors.affiliation: Department of Pathology.
authors.forename: Natopol
authors.initials: N
authors.lastname: Pornputtapong
authors.affiliation: Department of Pediatrics.
authors.forename: Zifeng
authors.initials: Z
authors.lastname: Mai
authors.affiliation: Department of Surgery.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ariyan
authors.affiliation: Department of Surgery.
authors.forename: Deepak
authors.initials: D
authors.lastname: Narayan
authors.affiliation: Department of Medicine.|Yale Cancer Center.
authors.forename: Harriet
authors.initials: H
authors.lastname: Kluger
authors.affiliation: Yale Center for Analytic Sciences.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Medicine.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Verma
authors.affiliation: Department of Medicine.
authors.forename: Rituparna
authors.initials: R
authors.lastname: Das
authors.affiliation: Department of Dermatology.
authors.forename: Antonella
authors.initials: A
authors.lastname: Bacchiocchi
authors.affiliation: Department of Dermatology.
authors.forename: Ruth
authors.initials: R
authors.lastname: Halaban
authors.affiliation: Department of Medicine.|Yale Cancer Center.
authors.forename: Mario
authors.initials: M
authors.lastname: Sznol
authors.affiliation: Department of Medicine.|Yale Cancer Center.|Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Madhav V
authors.initials: MV
authors.lastname: Dhodapkar
authors.affiliation: Department of Pediatrics.|Yale Cancer Center.
authors.forename: Kavita M
authors.initials: KM
authors.lastname: Dhodapkar