Fatty liver disease affects anti-tumor immunity and response to anti-PD1 therapy of HCC

Hepatocellular carcinoma (HCC) is a cancer associated with underlying inflammation. While infection with hepatitis B or C virus continues to be an important risk factor for HCC non-alcoholic fatty liver disease (NAFLD) is rising rapidly, in parallel with the global obesity epidemic, and driving an overall increase in HCC incidence and deaths worldwide. Immune checkpoint inhibitor-based immunotherapy is a promising treatment for HCC patients with advanced disease. Immune checkpoint inhibitors as single agent (pembrolizumab) or in combination (atezolizumab plus bevacizumab and nivolumab/ipilimumab) are currently approved in the United States by the Food and Drug Administration for the treatment of patients with HCC irrespective of their underlying liver disease. However, the different causes of liver disease in HCC may influence tumor biology as well as the constituency of its immune microenvironment. In the past my group has shown that linoleic acid, which accumulates in NALFD can specifically cause CD4 T cell death and thereby promote tumor growth in murine models of HCC (Ma et al Nature 2016). In a very recent study Pfister et al. showed anti-PD1 treatment led to an increased incidence of HCC in mice with NALFD (Pfister et al. Nature 2021) and my own group studies whether NAFLD will also impair adaptive immune responses in mice a therapeutic setting. Steatohepatitis was induced using two different diets (CDAA and MCD). Mice with orthotopically injected tumors were treated with an m-RNA based tumor vaccine or anti-OX40. While steatosis had no effect on the growth of subcutaneous tumors, mice with diet-induced steatohepatitis did not respond to immunotherapy and flow cytometry analysis of liver tumors revealed reduced CD4 T cells and effector memory cells in mice with vs without steatohepatitis (Heinrich et al. Gastroenterology 2021). In recent studies we also studied a possible effect of steatohepatitis on platelets since non-alcoholic fatty liver disease (NAFLD), causes platelet activation. Unexpectedly and in contrast to what had been described in the past in the absence of steatohepatitis, we noticed enhanced HCC growth after blocking platelet function or platelet depletion in multiple murine NAFLD models, revealing platelets’ anti-tumor function. Preliminary data suggest that anti-CD40L, which accumulates in platelets may exert anti-tumor function in mice with NAFLD and we are currently studying this mechanism in more detail.