The targets for tumour immunotherapy mediated by the inflammatory properties of vesicular stomatitis virus (VSV)-based antigen presentation depend upon the tumour’s anatomical site


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Richard Vile1,
1Mayo Clinic, Rochester, USA

Abstract

Although we initially used vesicular stomatitis virus as a direct oncolytic agent, we also observed that it serves as an excellent inflammatory adjuvant, allowing priming of T cell responses against tumour antigens encoded within the virus. As a result, 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 tumours (VSV-N-RAS/VSV-CYT-C/VSV-TYRP-1) was completely ineffective against intra-cranial (i.c.) B16 tumours. In contrast, a different combination of VSV-expressed antigens isolated from the ASMEL (VSV-HIF-2α/VSV-SOX-10/VSV-C-MYC/VSV-TYRP-1) was highly effective against i.c. B16 tumours, but had no efficacy against s.c B16 tumours. Correspondingly, i.c. B16 tumours expressed a HIF-2αHi, SOX-10Hi, c-mycHi, TYRP1, N-RASlo CYT-Clo antigen profile, which differed significantly from the HIF-2αlo, SOX-10lo, c-myclo, TYRP1, N-RASHi CYT-CHi phenotype of s.c. B16 tumours, and which was imposed upon the tumour cells by CD11b+ cells within the local tumour 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 tumour within 25-30 days. Our data show that tumours 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 tumour growth profoundly affects the profile of potential immunogens expressed by the tumour cells. This has important implications for the design of therapies which target the same histological type of tumour growing in different locations.

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