Arid5a orchestrates immune evasion of pancreatic cancer via the Ido1-–mediated tryptophan metabolism

Abstract

Abstract Although pancreatic ductal adenocarcinoma (PDAC) is known to be “immunologically cold” tumors, in which the presence of immune cells and their activity are limited by the tumor microenvironment, the immunological nature of this cancer is still largely unknown. AT-rich interaction domain-containing protein 5a (Arid5a) was identified as an RNA-binding protein that plays significant roles in the development of inflammatory diseases via the augmentation of IL-6 signaling. However, the role of Arid5a in cancer remains elusive. To clarify the role of Arid5a in cancer, we used the well-established mouse PDAC model KPC cells, bearing KRAS/TP53 mutations. We found that although KPC cells lacking Arid5a (Arid5a-KO) had similar growth rates as wild-type (WT) KPC cells when subcutaneously inoculated into immunodeficient mice, Arid5a-KO cells had remarkably impaired their growth in immunocompetent mice. Here, we show that Arid5a promotes immunosuppressive tumor microenvironment by inducing the infiltration of regulatory T cells and granulocytic myeloid-derived suppressor cells; and inhibiting the activation of CD8+T lymphocytes. Interestingly, we observed that Arid5a-KO KPC cells had significantly lower expression of indoleamine 2,3-dioxygenase 1 (Ido1) compared with WT KPC cells. Mechanistically, we identified that Arid5a stabilizes Ido1 mRNA through binding to its 3′-untranslated region, and augments the production of kynurenine, which is an immunoregulatory metabolite of Ido1-mediated tryptophan catabolism. Our findings indicate Arid5a as a crucial molecule involved in the immune evasion of PDAC which can be exploited for immunotherapy in malignant pancreatic cancer.