Virus-Specific CD8 T Cells Infiltrate Melanoma Lesions and Retain Function Independently of PD-1 Expression

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.