KRAS Inhibitors in Pancreas Cancer: Facts and Hopes about the Immunotherapy We’ve All Been Waiting For

Abstract Oncogenic RAS drives an immunosuppressive tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC). Inhibition of RAS signaling, as is now possible with an ever-increasing pharmaceutical portfolio, not only directly blocks tumors cells but also reverses immunosuppression, enabling infiltration of cytotoxic T cells and major alteration of the tumor microenvironment. In preclinical studies, the full anti-tumor effects of RAS inhibitors depend on T cells such that regressions in mice lacking T cells (or cross-presenting dendritic cells) are less deep and less durable than those in T cell-replete mice. Moreover, RAS inhibitors given with immune checkpoint blockade and immune agonists produce even more potent anti-tumor effects, especially in tumors with some amount of baseline T cell infiltration. These findings set the stage for testing RAS inhibitors and immunotherapy in combination for pancreatic ductal carcinoma (PDAC), which is otherwise refractory to immunotherapy. Other immune partners might include vaccines, bispecific antibodies, and cell therapy. A major clinical opportunity eventually would be combining RAS inhibitors and immunotherapy in the adjuvant, neo-adjuvant, and interception settings, provided this new class of drugs is developed keeping its immune modulatory power in mind.