title: Virus-Specific CD8+T Cells Infiltrate Melanoma Lesions and Retain Function Independently of PD-1 Expression.
abstract: It is well known that CD8+tumor-infiltrating lymphocytes (TILs) are correlated with positive prognoses in cancer patients and are used to determine the efficacy of immune therapies. Although it is generally assumed that CD8+TILs will be tumor-associated Ag (TAA) specific, it is unknown whether CD8+T cells with specificity for common pathogens also infiltrate tumors. If so, the presence of these T cells could alter the interpretation of prognostic and diagnostic TIL assays. We compared TAA-specific and virus-specific CD8+T cells in the same tumors using murine CMV, a herpesvirus that causes a persistent/latent infection, and vaccinia virus, a poxvirus that is cleared by the host. Virus-specific CD8+TILs migrated into cutaneous melanoma lesions during acute infection with either virus, after a cleared vaccinia virus infection, and during a persistent/latent murine CMV infection. Virus-specific TILs developed independently of viral Ag in the tumor and, interestingly, expressed low or intermediate levels of full-length PD-1 in the tumor environment. Importantly, PD-1 expression could be markedly induced by Ag but did not correlate with dysfunction for virus-specific TILs, in sharp contrast to TAA-specific TILs in the same tumors. These data suggest that CD8+TILs can reflect an individual's immune status, rather than exclusively representing TAA-specific T cells, and that PD-1 expression on CD8+TILs is not always associated with repeated Ag encounter or dysfunction. Thus, functional virus-specific CD8+TILs could skew the results of prognostic or diagnostic TIL assays.
authors.affiliation: Department of Microbiology and Immunology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Dan A
authors.initials: DA
authors.lastname: Erkes
authors.affiliation: Department of Microbiology and Immunology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Corinne J
authors.initials: CJ
authors.lastname: Smith
authors.affiliation: Department of Microbiology and Immunology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Nicole A
authors.identifier: 0000-0003-0285-0853
authors.initials: NA
authors.lastname: Wilski
authors.affiliation: Department of Microbiology and Immunology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.|Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal; and.|ICVS/3Bs, PT Government Associated Laboratory, 4710-057 Braga/Guimarães, Portugal.
authors.forename: Sofia
authors.initials: S
authors.lastname: Caldeira-Dantas
authors.affiliation: Department of Microbiology and Immunology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Toktam
authors.initials: T
authors.lastname: Mohgbeli
authors.affiliation: Department of Microbiology and Immunology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107; christopher.snyder@jefferson.edu.
authors.forename: Christopher M
authors.identifier: 0000-0003-1370-7198
authors.initials: CM
authors.lastname: Snyder
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005434:Flow Cytometry; D006566:Herpesviridae Infections / Q000150:complications / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008546:Melanoma, Experimental / Q000150:complications / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018146:Muromegalovirus / Q000276:immunology; D016133:Polymerase Chain Reaction; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis / Q000276:immunology; D014615:Vaccinia / Q000150:complications / Q000276:immunology; D014616:Vaccinia virus / Q000276:immunology; D014777:Virus Diseases / Q000150:complications* / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor