Campbell et al. showed CCR8 to be a marker for a subset of highly suppressive Tregs. The frequency of CCR8+ cells was higher in patients’ tumors than in their blood, a distinction not observed with other Treg markers. CCR8 expression on effector T cells (both CD4+ and CD8+) was low, and the frequency of proinflammatory cytokine-producing cells was lower in CCR8+ than in CCR8- populations. Anti-CCR8 antibody depleted Tregs from human tumor explants. In mice, provided the Fc receptor binding function was intact, anti-CCR8 antibodies prevented tumor growth, enhanced antitumor immune memory, synergized with anti-PD-1, and preserved Tregs in non-tumor tissue.
Contributed by Margot O’Toole
ABSTRACT: FOXP3+ Regulatory T cells (Tregs) play a critical role in mediating tolerance to self-antigens and can repress antitumor immunity through multiple mechanisms. Therefore, targeted depletion of tumor resident Tregs is warranted to promote effective antitumor immunity while preserving peripheral homeostasis. Here we propose the chemokine receptor CCR8 as one such optimal tumor Treg target. CCR8 was expressed by Tregs in both murine and human tumors, and unlike CCR4, a Treg depletion target in the clinic, CCR8 was selectively expressed on suppressive tumor Tregs and minimally expressed on proinflammatory effector T cells (Teffs). Preclinical mouse tumor modeling showed that depletion of CCR8+ Tregs through an FcyR engaging anti-CCR8 antibody, but not blockade, enabled dose-dependent, effective, and long-lasting antitumor immunity that synergized with PD-1 blockade. This depletion was tumor Treg-restricted, sparing CCR8+ T cells in the spleen, thymus, and skin of mice. Importantly, Fc-optimized, non-fucosylated (nf) anti-human CCR8 antibodies specifically depleted Tregs and not Teffs in ex vivo tumor cultures from primary human specimens. These findings suggest that anti-CCR8-nf antibodies may deliver optimal tumor-targeted Treg depletion in the clinic, providing long term antitumor memory responses while limiting peripheral toxicities.