Cutaneous squamous cell carcinoma (cSCC) is one of the most common human cancers whose estimated deaths approach or exceed that of melanoma. Immune inhibitory receptor antagonism through blockade of programmed death receptor 1 (PD-1) or its ligand PD-L1, has revolutionized the treatment of cSCC
however, approximately half of the patients still fail to respond. Inhibitory receptor programmed death-1 homolog (PD-1H) (also known as VISTA) functions to control T cell and myeloid cell functions in pre-clinical cancer studies. Current cancer clinical trials using anti-VISTA blocking antibodies are ongoing. We sought to determine the extent of VISTA expression in cSCCs and correlate its expression with PD-L1. Using multiplexed quantitative immunofluorescence of primary cSCC tissues (n=76) we found that VISTA is expressed in 48% of cSCCs and PD-L1 is expressed in 58% of cSCCs. We found high VISTA expression, more than PD-L1 expression, was correlated with greater T cell infiltration and activation as measured by proliferation marker Ki-67 and cytotoxic marker Granzyme B. Furthermore, there was no significant correlation between VISTA and PD-L1 co-expression within the same cSCCs, suggesting individual tumors have distinct immunosuppressive microenvironments. These findings provide rationale for targeting VISTA for cSCC cancer immunotherapy.