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.