Inhibition of ITGB6 stimulates potent anti-tumor responses in immunocompetent mouse models of head and neck squamous cell carcinoma and pancreatic adenocarcinoma.

ITGB6, the gene encoding the β6 subunit of integrin αvβ6, is a potent prognostic marker across multiple cancer types. As a major activator of latent TGFβ and a potent modulator of the tumor immune environment, αvβ6, and consequently, ITGB6, has considerable therapeutic implications. ITGB6 is highly upregulated in squamous cell carcinomas and pancreatic adenocarcinomas, where it disrupts tumor-immune cell signaling. We identify ITGB6 as a potent clinical prognostic marker of anti-tumor immune response and were able to recapitulate the immune-mediated anti-tumor effect of ITGB6 in pre-clinical mouse models. Genetic knockout of ITGB6 in heterotopically-injected head and neck squamous cell carcinoma and pancreatic adenocarcinoma cell lines shows markedly reduced tumor progression and immunogenic cytokine profiles in immunocompetent mice. Additionally, co-cultures of human head and neck squamous cell carcinoma and pancreatic adenocarcinoma with human T-cells show increased T-cell killing upon cancer cell ITGB6 inhibition. Colony formation experiments give further evidence that the reduced tumor growth observed upon ITGB6 inhibition in vivo is through immunological clearance of cancer cells and not merely through intrinsic factors. Analysis of The Cancer Genome Atlas (TCGA) reveals the high prognostic value of ITGB6 on overall survival and that high ITGB6 expression in patients is associated with an inferior response to α-PD-1 and α-PD-L1 immune checkpoint blockade. The potent anti-tumor immune response observed both in vitro and in vivo upon ITGB6 inhibition, combined with analysis of RNA-seq data from immune checkpoint blockade-treated patients, encourages the development of ITGB6 blockade and immunotherapy combination regimens. Further pre-clinical studies should facilitate translation of our findings into therapeutic clinical trials for treating immunotherapy-resistant cancers.