Differential control of human Treg and effector T cells in tumor immunity by Fc-engineered anti-CTLA-4 antibody
Differential control of human Treg and effector T cells in tumor immunity by Fc-engineered anti-CTLA-4 antibody
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DOI：
10.1073/pnas.1812186116
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发表时间：
2019-01-08
影响因子：
11.1
通讯作者：
Sakaguchi, Shimon
中科院分区：
文献类型：
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作者：
Ha, Danbee;Tanaka, Atsushi;Sakaguchi, Shimon
抗CTLA-4 mAb在增强人类肿瘤免疫中是有效的。CTLA-4在活化后由常规T细胞表达，并且由天然存在的FOXP 3（+）CD 4（+）Treg细胞组成性表达，这提出了抗CTLA-4 mAb如何在肿瘤免疫中差异化地控制这些功能相反的T细胞群体的问题。在这里，我们发现FOXP 3（高）有效抑制效应Treg细胞在黑色素瘤组织中丰富，表达CTLA-4的水平高于肿瘤浸润性CD 8（+）T细胞。在体外肿瘤抗原刺激来自健康个体或黑素瘤患者的外周血单核细胞后，具有高抗体依赖性细胞介导的细胞毒性（ADCC）和细胞吞噬作用（ADCP）活性的Fc区修饰的抗CTLA-4 mAb选择性地耗尽CTLA-4（+）FOXP 3（+）Treg细胞，并因此扩增肿瘤抗原特异性CD 8（+）T细胞。重要的是，只有当抗原刺激从抗体处理延迟几天以使CTLA-4（+）激活的效应CD 8（+）T细胞免于mAb介导的杀伤时，才发生扩增。类似地，在荷瘤小鼠中，高ADCC/ADCP抗CTLA-4 mAb治疗与延迟的肿瘤抗原疫苗接种显著延长了它们的生存期，并显著增加了肿瘤浸润性CD 8（+）T细胞的细胞因子产生，而抗体治疗与疫苗接种同时进行则没有。经修饰以表现出较低或无Fc结合活性的抗CTLA 4 mAb未能表现出这种时间依赖性的体外和体内免疫增强。因此，高ADCC抗CTLA-4 mAb能够选择性耗尽效应Treg细胞，并根据效应CD 8（+）T细胞的CTLA-4表达状态激发肿瘤免疫。这些发现有助于设计具有靶向FOXP 3（+）Treg细胞和肿瘤反应性效应T细胞通常表达的分子的mAb的癌症免疫疗法。
Anti-CTLA-4 mAb is efficacious in enhancing tumor immunity in humans. CTLA-4 is expressed by conventional T cells upon activation and by naturally occurring FOXP3(+)CD4(+) Treg cells constitutively, raising a question of how anti-CTLA-4 mAb can differentially control these functionally opposing T cell populations in tumor immunity. Here we show that FOXP3(high) potently suppressive effector Treg cells were abundant in melanoma tissues, expressing CTLA-4 at higher levels than tumor-infiltrating CD8(+)T cells. Upon in vitro tumor-antigen stimulation of peripheral blood mononuclear cells from healthy individuals or melanoma patients, Fc-region-modified anti-CTLA-4 mAb with high antibody-dependent cell-mediated cytotoxicity (ADCC) and cellular phagocytosis (ADCP) activity selectively depleted CTLA-4(+)FOXP3(+) Treg cells and consequently expanded tumor-antigen-specific CD8(+)T cells. Importantly, the expansion occurred only when antigen stimulation was delayed several days from the antibody treatment to spare CTLA-4(+) activated effector CD8(+)T cells from mAb-mediated killing. Similarly, in tumor-bearing mice, high-ADCC/ADCP anti-CTLA-4 mAb treatment with delayed tumor-antigen vaccination significantly prolonged their survival and markedly elevated cytokine production by tumor-infiltrating CD8(+)T cells, whereas antibody treatment concurrent with vaccination did not. Anti-CTLA4 mAb modified to exhibit a lesser or no Fc-binding activity failed to show such timing-dependent in vitro and in vivo immune enhancement. Thus, high ADCC anti-CTLA-4 mAb is able to selectively deplete effector Treg cells and evoke tumor immunity depending on the CTLA-4-expressing status of effector CD8(+)T cells. These findings are instrumental in designing cancer immunotherapy with mAbs targeting the molecules commonly expressed by FOXP3(+) Treg cells and tumor-reactive effector T cells.