The Profile of Tumor Antigens Which Can be Targeted by Immunotherapy Depends Upon the Tumor's Anatomical Site
Authors: Vanesa Alonso-Camino, Karishma Rajani, Timothy Kottke, Diana Rommelfanger-Konkol, Shane Zaidi, Jill Thompson, Jose Pulido, Elizabeth Ilett, Oliver Donnelly, Peter Selby, Hardev Pandha, Alan Melcher, Kevin Harrington, Rosa Maria Diaz, Richard Vile
Journal: Molecular Therapy (2014)

Previously, we showed that vesicular stomatitis virus (VSV) engineered to express a cDNA library from human melanoma cells (ASMEL, Altered Self Melanoma Epitope Library) was an effective systemic therapy to treat subcutaneous (s.c.) murine B16 melanomas. Here, we show that intravenous treatment with the same ASMEL VSV-cDNA library was an effective treatment for established intra-cranial (i.c.) melanoma brain tumors. The optimal combination of antigens identified from the ASMEL which treated s.c. B16 tumors (VSV-N-RAS+VSV-CYTC-C+VSV-TYRP-1) was ineffective against i.c. B16 brain tumors. In contrast, combination of VSV-expressed antigens—VSV-HIF-2α+VSV-SOX-10+VSV-C-MYC+VSV-TYRP1—from ASMEL which was highly effective against i.c. B16 brain tumors, had no efficacy against the same tumors growing subcutaneously. Correspondingly, i.c. B16 tumors expressed a HIF-2αHi, SOX-10Hi, c-mycHi, TYRP1, N-RASloCytclo antigen profile, which differed significantly from the HIF-2αlo, SOX-10lo, c-myclo, TYRP1, N-RASHiCytcHi phenotype of s.c. B16 tumors, and was imposed upon the tumor cells by CD11b+ cells within the local brain tumor microenvironment. Combining T-cell costimulation with systemic VSV-cDNA treatment, long-term cures of mice with established i.c. tumors were achieved in about 75% of mice. Our data show that the anatomical location of a tumor profoundly affects the profile of antigens that it expresses. Previously, we showed that vesicular stomatitis virus (VSV) engineered to express a cDNA library from human melanoma cells (ASMEL, Altered Self Melanoma Epitope Library) was an effective systemic therapy to treat subcutaneous (s.c.) murine B16 melanomas. Here, we show that intravenous treatment with the same ASMEL VSV-cDNA library was an effective treatment for established intra-cranial (i.c.) melanoma brain tumors. The optimal combination of antigens identified from the ASMEL which treated s.c. B16 tumors (VSV-N-RAS+VSV-CYTC-C+VSV-TYRP-1) was ineffective against i.c. B16 brain tumors. In contrast, combination of VSV-expressed antigens—VSV-HIF-2α+VSV-SOX-10+VSV-C-MYC+VSV-TYRP1—from ASMEL which was highly effective against i.c. B16 brain tumors, had no efficacy against the same tumors growing subcutaneously. Correspondingly, i.c. B16 tumors expressed a HIF-2αHi, SOX-10Hi, c-mycHi, TYRP1, N-RASloCytclo antigen profile, which differed significantly from the HIF-2αlo, SOX-10lo, c-myclo, TYRP1, N-RASHiCytcHi phenotype of s.c. B16 tumors, and was imposed upon the tumor cells by CD11b+ cells within the local brain tumor microenvironment. Combining T-cell costimulation with systemic VSV-cDNA treatment, long-term cures of mice with established i.c. tumors were achieved in about 75% of mice. Our data show that the anatomical location of a tumor profoundly affects the profile of antigens that it expresses.