ISG15 and neoplasm: Indeed, in our preclinical tumor models we observed that the anti-tumor benefit of treating subcutaneously (s.c.)established B16 (BRAFWTPTENWT) and BPR20 (BRAFV600EPTEN-/-) melanomas in C57BL/6 mice with locally delivered ADU-S100 was improved by cotreatment with either a combination of ARG2/COX2/NOS2 pharmacologic inhibitors or with neutralizing/blocking antibodies against PD-L1 or ISG15 (a molecule that can mediate either pro- or anti-tumor effects as an extracellular cytokine-like mediator based on microenvironmental context (20)).