Fc-Optimized Anti-CCR8 Antibody Depletes Regulatory T Cells in Human Tumor Models

Area of Science:

• Immunology
• Oncology

Background:

• FOXP3+ regulatory T cells (Tregs) suppress antitumor immunity.
• Targeted Treg depletion is crucial for effective cancer immunotherapy.

Purpose of the Study:

• Identify and validate CCR8 as an optimal target for tumor-resident Treg depletion.
• Evaluate the efficacy of anti-CCR8 antibodies in promoting antitumor immunity.

Main Methods:

• Assessed CCR8 expression on Tregs and effector T cells (Teffs) in murine and human tumors.
• Utilized anti-CCR8 antibodies for Treg depletion in preclinical models and ex vivo human tumor cultures.
• Investigated the synergistic effects of anti-CCR8 therapy with PD-1 blockade.

Main Results:

• CCR8 is selectively expressed on tumor-resident Tregs, not on proinflammatory Teffs.
• Anti-CCR8 antibody-mediated depletion of Tregs enhanced antitumor immunity in mouse models.
• Depletion was tumor-specific, sparing Tregs in peripheral organs.
• Fc-optimized, nonfucosylated (nf) anti-CCR8 antibodies effectively depleted Tregs ex vivo from human tumors.

Conclusions:

• CCR8 is a promising target for selective depletion of tumor-resident Tregs.
• Anti-CCR8-nf antibodies offer a potential strategy for cancer immunotherapy.
• This approach may enhance antitumor responses as monotherapy or in combination with checkpoint inhibitors.