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

Abstract

Abstract Regulatory T cells (Tregs) are 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 exerts anticancer effect in several cancers, but whether this pathway is involved in the progression of hepatocellular carcinoma (HCC) remains unclear. Here we determined CCR8+ Tregs in human TCC tissues and examined the anticancer effect and the underlying molecular mechanisms of CCR8 antagonist antibody, IPG0521m, in murine liver cancer model. Our results demonstrated marked increase of CCR8+ Tregs in human HCC tissues. Treatment of syngeinic liver cancer model with IPG0521m resulted in dramatic inhibition of tumor growth, associated with increased CD8+ T cells in the tumor tissues. Preliminary 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 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. Finally, IPG0521m exerted long-lasting anticancer effect and synergized with PD-1 antibody in tumor inhibition. In conclusion, IPG0521m inhibited liver cancer growth via reducing the immunosuppression of Tregs, thereby boosting anti-cancer immunity. Our study paves the way for the clinical study of CCR8 antagonist in HCC and other cancer therapy.