CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory

Significance Immunosuppressive Foxp3-expressing regulatory T cells (Tregs) in tumor tissues are assumed to be clonally expanding via recognizing tumor-associated antigens. By single-cell RNA sequencing, we have searched for the molecules that are specifically expressed by such multiclonal tumor Tregs, but not by tumor-infiltrating effector T cells or natural Tregs in other tissues. The search revealed the chemokine receptor CCR8 as a candidate. Treatment of tumor-bearing mice with cell-depleting anti-CCR8 antibody indeed selectively removed multiclonal tumor Tregs without affecting effector T cells or tissue Tregs, eradicating established tumors with induction of potent tumor-specific effector/memory T cells and without activating autoimmune T cells. Thus, specific depletion of clonally expanding tumor Tregs is clinically instrumental for evoking effective tumor immunity without autoimmune adverse effects.