Tumor-Associated Mast Cells Drive Immunosuppression and Resistance to Anti-PD-1 Therapy in Hepatocellular Carcinoma Through CCL17/CCR4-mediated Regulatory T-Cell Recruitment.

This study investigated how tumor-associated mast cells (TAMCs) contribute to immunosuppression and anti-PD-1 resistance in hepatocellular carcinoma (HCC). TAMC infiltration as well as the levels of stem cell factor (SCF) and various chemokines were measured in clinical specimens obtained from 59 HCC patients. The recruitment and maintenance of TAMCs by HCC-conditioned medium were examined, with a focus on the role of SCF in these processes. In addition, the chemotactic effect of CCL17 (secreted by activated TAMCs) on CCR4-expressing regulatory T cells (Tregs) was evaluated. The functional impact of the recruited Tregs was further assessed by examining their capacity to inhibit the proliferation of CD8+ T cells and to suppress the secretion of cytotoxic effector molecules. In vivo experiments were also conducted to evaluate the antitumor efficacy of combining anti-PD-1 antibodies with either cromolyn sodium or CCR4 antagonists. Analysis of HCC specimens revealed a marked accumulation of TAMCs, and the extent of TAMC infiltration was found to be positively correlated with both SCF and CCL17 levels. HCC cells were shown to actively recruit TAMCs and promote their proliferation through the secretion of SCF. Upon activation, TAMCs released CCL17, which potently chemotaxed Tregs in a CCR4-dependent manner and subsequently suppressed the antitumor activity of CD8+ T cells. In vivo, the combination of anti-PD-1 antibodies with cromolyn sodium or CCR4 antagonists yielded a synergistic antitumor effect, outperforming each agent used as monotherapy. Overall, these findings suggest that TAMCs drive immune suppression and confer resistance to anti-PD-1 therapy in HCC through CCL17/CCR4-mediated Treg recruitment.