Targeting the Immunosuppressive Tumor Microenvironment for Colorectal Cancer Treatment

Project Summary/Abstract Despite notable improvements in colorectal cancer (CRC) treatment, the prognosis of patients with metastatic CRC (mCRC) remains poor, with a median overall survival of approximately 30 months. Immunotherapy such as immune checkpoint blockade (ICB) represents a novel therapeutic approach for a variety of cancers including mCRC with microsatellite instability-high (MSI-H). However, ICB therapy shows little or no clinical activity in approximately 95% of patients with microsatellite-stable (MSS) mCRC. We and others have shown that administration of ketogenic diets (KD) and the ketone body ?-hydroxybutyrate (?HB), enhance the anticancer effects of ICB for CRC in mouse tumor models. However, whether KD/?HB can improve ICB therapy for CRCs with MSS is not known. Moreover, the impact of altered ketogenesis on the immunosuppressive TME remains to be defined and represents a major gap in our understanding of tumor immunoresistance. Cancer associated fibroblasts (CAFs), the major component of tumor stromal cells, play a critical role in the tumor suppressive TME. We have shown that downregulated ketogenesis is a hallmark in CRC TME. Activation of oncogenic signaling (e.g., WNT and KRAS) decreases ketogenesis in CRCs. Restoration of ketogenesis inhibits aerobic glycolytic activity in CAFs and inhibits histone deacetylase 1 (HDAC1)/KLF5 dependent CAF proliferation and cytokine expression and secretion. Importantly, we showed that KD improves the immunosuppressive TME, as noted by increased CD8+ T cell and NK cell infiltration and decreased M2 macrophage populations, and enhances the efficacy of ICB. Our findings demonstrate a previously unknown association of downregulated de novo ketogenesis, metabolic alteration and CAF functions in the TME and have identified cancer ketogenesis as a potential immunotherapeutic target. Based on this surprising and novel finding, we hypothesize that downregulated de novo ketogenesis is a unique immune evasion mechanism in the TME. Our long-term goal is to identify aberrant metabolism within the cancer and/or stromal compartments that can be used to improve the treatment of patients with mCRC. We speculate that oncogenic WNT/β-catenin and KRAS inhibit ketogenesis in CRC TME, which leads to the increased CAF proliferation and cytokine production and thus resistance to ICB and promotion of CRC progression. To examine our central hypothesis, we have assembled a highly collaborative team with significant expertise in CRC progression and treatment, tumor metabolism, tumor immunity and neoplastic ketogenesis, and planned experiments which will determine the impact of alterations of ketogenesis on the immunosuppressive TME in CRC, delineate ketogenic control of CAF metabolism, proliferation, and functional potency in the TME, and define the impact of targeting ketogenic metabolism on the efficacy of ICB for CRC. Ultimately, our findings will: i) revolutionize our concept of CRC TME and immunoresistance; ii) significantly advance paradigms regarding the effects of KD/?HB; and iii) may provide a novel CRC treatment strategy by targeting dysregulated ketogenic metabolism.