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

Introduction: Accumulation of regulatory T (Treg) cells, an immunosuppressive population, limits the efficacy of immunotherapy in NSCLC. C-C motif chemokine receptor 8 (CCR8) is selectively expressed in tumor-infiltrating Treg cells and is, therefore, considered an ideal target.

Methods: The efficacy and safety of anti-CCR8 monotherapy and its combination with programmed cell death protein-1 (PD1) inhibitor were evaluated in four NSCLC-bearing mice models. To track the dynamic changes in tumor microenvironment, we performed the single-cell RNA sequencing, the single-cell T-cell receptor sequencing analysis, the flow cytometry, the multi-color immunofluorescence, and the Luminex assay on tumors after three, seven, 14, and 21 days of different treatment regimens. Then, in vitro and in vivo experiments were applied to validate our findings and explore molecular mechanisms of the synergistic effects.

Results: Across four NSCLC-bearing mice models, the combination of CCR8 antibody and PD1 inhibitor significantly reduced tumor growth (p < 0.05) without obvious mouse body weight drops and systemic cytokine storm. The anti-CCR8 therapy synergizes with PD1 blockade by remodeling the tumor microenvironment and disrupting CCR8+Treg-C-C motif chemokine ligand 5 (CCL5)+ dendritic cells (DC) interaction. Mechanistically, therapeutic depletion of CCR8+Treg cells combined with PD1 inhibitor extremely increased interleukin-12 secretion by the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway activation on CCL5+ DCs, thereby promoting cytotoxic activity of CD8+ T cells. The therapeutic potential of the CCR8 antibody LM108 in combination with immunotherapy was observed in clinical patients with advanced NSCLC.

Conclusion: Overall, CCR8 expression on tumor-infiltrating Treg cells is correlated with immunosuppressive function on DCs and CD8+ T cells, thus impeding antitumor immunity.