靶向肿瘤微环境中的 GARP-LTGFβ 轴通过增强 CD8 T 细胞抗肿瘤免疫来增强 PD-1 阻断。
Selective targeting of GARP-LTGFβ axis in the tumor microenvironment augments PD-1 blockade via enhancing CD8 T cell antitumor immunity.
机构信息
College of Medicine, The Ohio State University, Columbus, Ohio, USA.
Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center - Arthur G James Cancer Hospital and Richard J Solove Research Institute, The Ohio State University, Columbus, Ohio, USA.
出版信息
J Immunother Cancer. 2022 Sep;10(9). doi: 10.1136/jitc-2022-005433.
BACKGROUND
Immune checkpoint blockade (ICB) has revolutionized cancer immunotherapy. However, most patients with cancer fail to respond clinically. One potential reason is the accumulation of immunosuppressive transforming growth factor β (TGFβ) in the tumor microenvironment (TME). TGFβ drives cancer immune evasion in part by inducing regulatory T cells (Tregs) and limiting CD8 T cell function. Glycoprotein-A repetitions predominant (GARP) is a cell surface docking receptor for activating latent TGFβ1, TGFβ2 and TGFβ3, with its expression restricted predominantly to effector Tregs, cancer cells, and platelets.
METHODS
We investigated the role of GARP in human patients with cancer by analyzing existing large databases. In addition, we generated and humanized an anti-GARP monoclonal antibody and evaluated its antitumor efficacy and underlying mechanisms of action in murine models of cancer.
RESULTS
We demonstrate that GARP overexpression in human cancers correlates with a tolerogenic TME and poor clinical response to ICB, suggesting GARP blockade may improve cancer immunotherapy. We report on a unique anti-human GARP antibody (named PIIO-1) that specifically binds the ligand-interacting domain of all latent TGFβ isoforms. PIIO-1 lacks recognition of GARP-TGFβ complex on platelets. Using human (encoding GARP) knock-in mice, we find that PIIO-1 does not cause thrombocytopenia; is preferentially distributed in the TME; and exhibits therapeutic efficacy against GARP and GARP cancers, alone or in combination with anti-PD-1 antibody. Mechanistically, PIIO-1 treatment reduces canonical TGFβ signaling in tumor-infiltrating immune cells, prevents T cell exhaustion, and enhances CD8 T cell migration into the TME in a C-X-C motif chemokine receptor 3 (CXCR3)-dependent manner.
CONCLUSION
GARP contributes to multiple aspects of immune resistance in cancer. Anti-human GARP antibody PIIO-1 is an efficacious and safe strategy to block GARP-mediated LTGFβ activation, enhance CD8 T cell trafficking and functionality in the tumor, and overcome primary resistance to anti-PD-1 ICB. PIIO-1 therefore warrants clinical development as a novel cancer immunotherapeutic.
背景
免疫检查点阻断（ICB）彻底改变了癌症免疫疗法。然而，大多数癌症患者在临床上没有反应。一个潜在的原因是肿瘤微环境（TME）中积累了免疫抑制性转化生长因子β（TGFβ）。TGFβ 通过诱导调节性 T 细胞（Tregs）和限制 CD8 T 细胞功能，在一定程度上推动了癌症免疫逃逸。糖蛋白-A 重复占主导地位（GARP）是一种细胞表面对接受体，可激活潜伏的 TGFβ1、TGFβ2 和 TGFβ3，其表达主要局限于效应性 Tregs、癌细胞和血小板。
方法
我们通过分析现有的大型数据库研究了 GARP 在人类癌症患者中的作用。此外，我们生成并人源化了一种抗 GARP 单克隆抗体，并在癌症的小鼠模型中评估了其抗肿瘤疗效和作用机制。
结果
我们证明，人类癌症中 GARP 的过表达与耐受性 TME 和对 ICB 的临床反应不良相关，这表明 GARP 阻断可能改善癌症免疫疗法。我们报告了一种独特的抗人 GARP 抗体（命名为 PIIO-1），它特异性结合所有潜伏 TGFβ 同种型的配体相互作用域。PIIO-1 不识别血小板上的 GARP-TGFβ 复合物。使用人 GARP 敲入小鼠，我们发现 PIIO-1 不会引起血小板减少症；优先分布在 TME 中；并且单独或与抗 PD-1 抗体联合使用时，对 GARP 和 GARP 癌症具有治疗效果。从机制上讲，PIIO-1 治疗可降低肿瘤浸润免疫细胞中的经典 TGFβ 信号传导，防止 T 细胞衰竭，并以 C-X-C 基序趋化因子受体 3（CXCR3）依赖性方式增强 CD8 T 细胞向 TME 的迁移。
结论
GARP 有助于癌症中多种免疫抵抗方面。抗人 GARP 抗体 PIIO-1 是一种有效且安全的策略，可阻断 GARP 介导的 LTGFβ 激活，增强 CD8 T 细胞在肿瘤中的迁移和功能，并克服对抗 PD-1 ICB 的原发性耐药。因此，PIIO-1 有必要作为一种新型癌症免疫疗法进行临床开发。
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