Selective Depletion of CCR8+Treg Cells Enhances the Antitumor Immunity of Cytotoxic T Cells in Lung Cancer by Dendritic Cells

Accumulation of regulatory T (Treg) cells, an immunosuppressive population, limits the efficacy of immunotherapy in non-small cell lung cancer (NSCLC). C-C Motif Chemokine Receptor 8 (CCR8) is selectively expressed in tumor-infiltrating Treg cells and, thus considered an ideal target. Across four NSCLC-bearing mice models, the combination of CCR8 antibody and programmed cell death protein-1 (PD1) inhibitor significantly reduced tumor growth without obvious mouse body weight drops and systemic cytokine storm. The single-cell RNA and T-cell receptor sequencing analysis demonstrated that anti-CCR8 therapy synergizes with PD1 blockade by remodeling the tumor microenvironment and disrupting CCR8+Treg – CCL5+ dendritic cells (DC) interaction. Mechanistically, therapeutic depletion of CCR8+Treg cells combined with PD1 inhibitor extremely increased interleukin-12 secretion by the JAK-STAT pathway activation on CCL5+ DCs, thereby promoting cytotoxic activity of CD8+ T cells. The therapeutic potential of the CCR8 antibody LM-108 in combination with immunotherapy was observed in clinical patients with advanced NSCLC. Overall, CCR8 expression on tumor-infiltrating Treg cells is correlated with immunosuppressive function on DCs and CD8+ T cells, thus impeding anti-tumor immunity.