Fc-Optimized Anti-CCR8 Antibody Depletes Regulatory T Cells in Human Tumor Models
Fc-Optimized Anti-CCR8 Antibody Depletes Regulatory T Cells in Human Tumor Models
复制标题
Fc段优化的抗CCR8抗体在人肿瘤模型中耗竭调节性T细胞
DOI：
10.1158/0008-5472.can-20-3585
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发表时间：
2021-06-01
期刊：
影响因子：
11.2
通讯作者：
Lan, Ruth Y.
中科院分区：
文献类型：
--
作者：
Campbell, Joseph R.;McDonald, Bryan R.;Lan, Ruth Y.
FOXP 3（+）调节性T细胞（Treg）在介导对自身抗原的耐受中起关键作用，并可通过多种机制抑制抗肿瘤免疫。因此，有必要靶向消耗肿瘤驻留TdR，以促进有效的抗肿瘤免疫，同时保持外周稳态。在这里，我们提出趋化因子受体CCR 8作为一个这样的最佳肿瘤Treg靶点。CCR 8在鼠和人肿瘤中均由TcR表达，并且与临床中的Treg耗竭靶CCR 4不同，CCR 8选择性地在抑制性肿瘤TcR上表达，并且在促炎效应T细胞（T-eff）上最低限度地表达。临床前小鼠肿瘤建模显示，通过Fc γ R接合抗CCR 8抗体而非阻断消除CCR 8（+）TcR，能够实现与PD-1阻断协同的剂量依赖性、有效和持久的抗肿瘤免疫。这种消耗是肿瘤Treg限制性的，保留了小鼠脾脏、胸腺和皮肤中的CCR 8（+）T细胞。重要的是，Fc优化的非岩藻糖基化（nf）抗人CCR 8抗体特异性地耗尽来自原代人样本的离体肿瘤培养物中的T-effs而不是T-effs。这些发现表明，抗CCR 8-nf抗体可以在临床上提供最佳的肿瘤靶向Treg耗竭，提供长期的抗肿瘤记忆反应，同时限制外周toxicity.Significance：这些发现表明，选择性耗竭调节性T细胞与抗CCR 8抗体可以提高抗肿瘤免疫反应作为单一疗法或与其他免疫疗法的组合。
FOXP3(+) regulatory T cells (Treg) 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 (T-eff). 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, nonfucosylated (nf) anti-human CCR8 antibodies specifically depleted Tregs and not T-effs 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.Significance: These findings show that selective depletion of regulatory T cells with an anti-CCR8 antibody can improve antitumor immune responses as a monotherapy or in combination with other immunotherapies.