The Profile of Tumor Antigens Which Can Be Targeted By Immunotherapy Depends Upon the Tumor's Anatomical Site

We have shown that VSV engineered to express a cDNA library from human melanoma cells (ASMEL, Altered Self Melanoma Epitope Library) was an effective systemic therapy for subcutaneous (s.c.) murine B16 melanomas (Pulido et al., Nat. Biotech. 2012, 30:337-43). Here we show that the combination of antigens identified from the ASMEL which successfully treated s.c. B16 tumors (VSV-N-RAS/VSV-CYT-C/VSV-TYRP-1) was completely ineffective against intra-cranial (i.c.) B16 tumors. In contrast, a different combination of VSV-expressed antigens isolated from the ASMEL (VSV-HIF-2alpha/VSV-SOX-10/VSV-C-MYC/VSV-TYRP-1) was highly effective against i.c. B16 tumors, but had no efficacy against s.c B16 tumors. Correspondingly, i.c. B16 tumors expressed a HIF-2alphaHi, SOX-10Hi, c-mycHi, TYRP1, N-RASlo CYT-Clo antigen profile, which differed significantly from the HIF-2alphalo, SOX-10lo, c-myclo, TYRP1, N-RASHi CYT-CHi phenotype of s.c. B16 tumors, and which was imposed upon the tumor cells by CD11b+ cells within the local tumor microenvironment in the brain. By combining T cell co-stimulation with systemic VSV-cDNA treatment, long term cures (>100days) of over 60% of mice with established i.c. melanomas were achieved, whereas control mice succumbed to tumor within 25-30 days. Our data show that tumors of the same histological type, but growing in different anatomical locations, represent a series of related, but antigenically distinct, ‘quasi-species’ because the site of tumor growth profoundly affects the profile of potential immunogens expressed by the tumor cells. This has important implications for the design of therapies which target the same histological type of tumor growing in different locations. the same histological type of tumor growing in different locations