CCR8 antagonist suppresses liver cancer progression via turning tumor-infiltrating Tregs into less immunosuppressive phenotype.

BACKGROUND: Regulatory T cells (Tregs) are the main immunosuppressive cells in tumor immune microenvironment (TIME). However, systemic Treg depletion is not favored due to the crucial role of Tregs in the maintenance of immune homeostasis and prevention of autoimmunity. Recently, CCR8 has been identified as a key chemokine receptor expressed on tumor-infiltrating Tregs and targeted blockade of CCR8 exerts anticancer effect in several cancer types, but whether this pathway is involved in the progression of hepatocellular carcinoma (HCC) remains unclear. METHODS: We determined the involvement of CCR8(+) Tregs in HCC using human HCC tissues and TCGA database, and examined the anticancer effect and the underlying molecular mechanisms of the CCR8 antagonist, IPG0521m, which was developed in house, in murine liver cancer model with flow cytometry, bulk and single-cell RNA sequencing and Real-Time PCR. RESULTS: Remarkable increase in CCR8(+) Tregs was observed in human HCC tissues. Treatment of syngeneic liver cancer model with IPG0521m resulted in dramatic inhibition of tumor growth, associated with increased CD8(+) T cells in tumor tissues. Bulk RNA sequencing analysis indicated that IPG0521m treatment resulted in remarkable increase in antitumor immunity. Furthermore, single-cell RNA sequencing analysis demonstrated that IPG0521m treatment resulted in a switch of Tregs from high immunosuppression to low immunosuppression phenotype, associated with elevated CD8(+) T and NK cell proliferation and cytotoxicity, and decreased myeloid-derived suppressor cells and tumor-associated macrophages in the tumor tissues. CONCLUSIONS: IPG0521m inhibited liver cancer growth via reducing the immunosuppressive function of Tregs, thereby boosting anti-cancer immunity. Our study paves the way for the clinical study of CCR8 antagonist in HCC and other cancers.