ITGB6 inhibition stimulates anti-tumor responses in immunocompetent mouse models of head & neck squamous cell carcinoma and pancreatic adenocarcinoma

Abstract

ITGB6, the gene encoding the {beta}6 subunit of integrin v{beta}6, is a potent prognostic marker across multiple cancer types. As a major activator of latent TGF{beta}, v{beta}6, and consequently, ITGB6, has considerable therapeutic implications due to the immunosuppressive effect that activated TGF{beta} has on the tumor microenvironment. The present study identifies ITGB6 as a potent target for inducing an immune-mediated anti-tumor response. ITGB6 is highly upregulated in various squamous cell carcinomas and pancreatic adenocarcinomas, allowing it to disrupt tumor-immune cell signaling, while avoiding the widespread side-effects of systemic TGF{beta} inhibition. Genetic knockout of ITGB6 in heterotopically injected head and neck squamous cell carcinoma and pancreatic adenocarcinoma cell lines showed markedly reduced tumor progression in immunocompetent mice. Additionally, co-cultures of human squamous cell carcinoma cell lines and human T-cells showed increased T-cell killing upon cancer cell ITGB6 inhibition. Colony formation experiments give further evidence that the reduction in 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) revealed not only the high prognostic value of ITGB6 on overall survival but also that high ITGB6 expression in patients is often associated with an inferior response to -PD-1 and -PD-L1 immune checkpoint blockade. The potent anti-tumor immune response observed both in vitro and in vivo upon ITGB6 inhibition, combined with our analysis of RNA-seq data from immune checkpoint blockade-treated patients, encourages the development of ITGB6 blockade and immunotherapy combination regimes. Further pre-clinical studies will serve to facilitate the translation of our findings into therapeutic clinical trials of combination therapies for treating immunotherapy-resistant cancers. Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/590156v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@162546aorg.highwire.dtl.DTLVardef@9422d6org.highwire.dtl.DTLVardef@17b4a5eorg.highwire.dtl.DTLVardef@14f903d_HPS_FORMAT_FIGEXP M_FIG C_FIG