Cytokines and B cells controlling immune tumor microenvironment in hepatocellular carcinoma

About This Grant

PROJECT SUMMARY Liver cancer is the third deadliest cancer type worldwide and ranks fifth in the U.S. with its annual fatality rate still on the rise. Hepatocellular carcinoma (HCC) is the most frequent form of liver cancer with limited treatment options and low five-year survival rate. Although HBV and HCV incidence and, thus, viral-driven HCC is declining, the obesity epidemic contributes to increasing numbers of obesity-driven HCC new cases in developed countries. While some success has been achieved with immune checkpoint inhibitors, to date they benefit only a small number of patients with liver cancer. Therefore, it is essential to identify new biomarkers and mechanisms and develop novel and more effective immunotherapies for HCC patients. Interleukin (IL)-27 is a cytokine that plays immunomodulatory roles in infection and autoimmunity controlling various immune cells, including B cells. Recent work from our laboratory showed that IL27/IL27R signaling promotes HCC by suppressing anti-cancer NK/ILC1 innate immune cell activation. Nevertheless, the role of IL27R signaling in control of B cell adaptive immune responses in HCC in vivo has never been investigated. Moreover, the role of B cells in liver cancer is not well understood, and B cells represent a “double edge sword” in tumor microenvironment (TME). Therefore, better understating of the mechanisms regulating anti-cancer B cell immune responses are essential for effective therapy development. Our new findings suggest that IL27R signaling directly regulates B cell immune responses in fatty liver- driven hepatocellular carcinoma. We have discovered that elimination of IL27R signaling in B cells suppressed tumor development in HCC in vivo mouse model. We made an unexpected observation that genetic or pharmacological inhibition of IL27R skews B cell activation toward more activated, anti-cancer state, which further enables pro-inflammatory tumor associated macrophages with anti-cancer properties. Here we propose to investigate cellular and molecular mechanisms of how IL27R signaling regulates tumor promoting versus anti-tumor B cell immune responses and test their role in the control of tumor microenvironment in HCC. We will use highly relevant to human metabolic dysfunction associated steatohepatitis (MASH)-HCC MUP-uPA mouse model combined with B cell specific ablation of IL27R and integrated array of cutting-edge transcriptomics, histological, immunological, molecular biology and imaging analyses. Pre-clinical models will be supplemented by human samples analyses to ensure translatability of our studies. Finally, we will test the efficacy and identify cellular and molecular mechanisms of IL27 signaling blockade in combination with an array of other immunotherapies, as a new therapeutic avenue for HCC. Overall, the proposed research will uncover novel mechanisms how IL27R signaling regulates B cell immunity and TME in HCC for potential inroads into HCC treatment and prevention. This work has strong translational potential with game-changing ramifications for HCC.