Cancer-associated fibroblasts induce immunotherapy resistance in hepatocellular carcinoma animal model

Abstract

Hepatocellular carcinoma is known to be a common predominant cancer in adults, especially in eastern countries. Immune response and cancer-associated fibroblasts (CAFs) have significant influences on tumor development. However, the interaction between CAFs and immunotherapy is unclear in hepatocellular carcinoma. We measured the number of activated fibroblasts in hepatocellular carcinoma samples and samples taken from normal liver tissues. A total of 20 patients' fresh hepatocellular carcinoma and normal tissues which were surrounding the tumor were obtained from the surgery and used for evaluating alpha-SMA expression. We investigated the effects of CAFs in anti-tumor immunity in hepatocellular carcinoma animal model. The effects of CAFs in inducing anti-PD-1 treatment resistance were also measured in a preclinical animal model. Activated fibroblasts were highly accumulated in hepatocellular carcinoma tissues but not in surrounding normal tissues. CAFs showed a significant tumor-promoting effect in an immunocompetent model. The infiltration and function of some immune cells like myeloid-derived suppressive cells and T-cells were increased by CAFs. CAFs also reduced the number and activation of tumor-infiltrating cytotoxic T-cell in tumor tissue. In the treatment model, tumors with a higher amount of CAFs had been insensitive to therapy with anti-PD-1. CAFs are potent inducers of immunosuppression in hepatocellular carcinoma. Depleting CAFs rescued the antitumor immunity in the hepatocellular model and could be a novel treatment to combine with the existing immunotherapy.