Abstract A095: Immunosuppressive plasmocytes regulate the development of NASH-induced HCC

Abstract

Abstract Hepatocellular carcinoma (HCC), a rather common and lethal malignancy, is the prevalent common form of liver cancer, associated with chronic tissue damage caused by fat accumulation, environmental toxicants, viral infections, inflammation and stress. Although at present, hepatitis virus infections are the primary HCC risk factors, they will soon be replaced by hypernutrition and ethanol consumption, both of which cause hepatic steatosis. According to a recent CDC report the incidence of HCC continues to grow at an alarming yearly rate, in part due to the obesity epidemic. This has sparked a considerable effort to understand how non-alcoholic fatty liver disease (NAFLD) and its more aggressive manifestation, non-alcoholic steatohepatitis (NASH), drive HCC development. Although, many studies have confirmed that NASH to HCC progression is inflammation dependent, the role of adaptive immune responses in NASH-promoted HCC is largely unknown. We recently identified a type of B cells in both mouse and human prostate cancer (PC), that have potent immunosuppressive properties. Ablation of these immunosuppressive plasmocytes (ISP), enables nearly complete elimination of large and advanced PC tumors upon treatment with the immunogenic chemotherapeutic oxaliplatin. ISP are IgA-producing plasmocytes that express the immunosuppressive molecules IL-10 and PD-L1. In PCa, generation of ISP is driven by TGFβ, which is produced in large amounts by αSMA+ CAF, which also produce the B cell chemoattractant CXCL13. We therefore examined whether ISP are present in other tumors that are rich in TGFβ (and CXCL13)-producing αSMA+ myofibroblasts and confirmed their presence in two mouse models of liver cancers that develop in the context of chronic inflammation and fibrosis. Meanwhile, a strong correlation between circulating IgA and the degree of liver fibrosis was observed in patients suffering from NASH. Interestingly, accumulation of IgA and IL-10 expressing plasmocytes precedes HCC development and is not seen in mice that develop simple steatosis. The depletion of IL-10 and PD-L1-expressing ISP in livers of NASH-afflicted mice resulted in at least a 50% decrease in tumor burden accompanied by CTL activation and infiltration. Thus, a combination of anti-PD-L1 or other ISP-depleting treatment with a suitable immunogenic chemotherapeutic agent may result in more extensive HCC regression. Citation Format: Shabnam Shalapour, Michael Karin. Immunosuppressive plasmocytes regulate the development of NASH-induced HCC [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A095.