美国基因泰克公司Namrata S. Patil等研究人员合作发现，抗TIGIT抗体通过髓系细胞和Treg细胞改善PD-L1阻断效果。2024年2月28日，《自然》杂志在线发表了这项成果。

研究人员发现阿替利珠单抗联合替瑞利尤单抗治疗患者时，瘤内巨噬细胞和调节性T细胞的高基线与更好的疗效相关，而与阿替利珠单抗单药治疗无关。血清样本分析显示，巨噬细胞活化与接受联合治疗的患者的临床获益有关。在小鼠肿瘤模型中，替瑞利尤单抗代用抗体通过Fcγ受体（FcγR）使肿瘤相关巨噬细胞、单核细胞和树突状细胞发炎，进而促使抗肿瘤CD8⁺T细胞从衰竭的效应样状态转变为更具记忆性的状态。

这些结果揭示了TIGIT检查点抑制剂重塑免疫抑制性肿瘤微环境的作用机制，并表明FcγR参与是抗TIGIT抗体开发的一个重要考虑因素。

据悉，替瑞利尤单抗是一种具有活性IgG1κ Fc的抗TIGIT抗体，在CITYSCAPE二期试验（ClinicalTrials.gov: NCT03563716）中，替瑞利尤单抗与阿替利珠单抗（抗PD-L1）联合治疗比单独使用阿替利珠单抗治疗的疗效更好。然而，关于这种联合疗法的应答机制仍未达成共识。

附：英文原文

Title: Anti-TIGIT antibody improves PD-L1 blockade through myeloid and Treg cells

Author: Guan, Xiangnan, Hu, Ruozhen, Choi, Yoonha, Srivats, Shyam, Nabet, Barzin Y., Silva, John, McGinnis, Lisa, Hendricks, Robert, Nutsch, Katherine, Banta, Karl L., Duong, Ellen, Dunkle, Alexis, Chang, Patrick S., Han, Chia-Jung, Mittman, Stephanie, Molden, Nandini, Daggumati, Pallavi, Connolly, Wendy, Johnson, Melissa, Abreu, Delvys Rodriguez, Cho, Byoung Chul, Italiano, Antoine, Gil-Bazo, Ignacio, Felip, Enriqueta, Mellman, Ira, Mariathasan, Sanjeev, Shames, David S., Meng, Raymond, Chiang, Eugene Y., Johnston, Robert J., Patil, Namrata S.

Issue&Volume: 2024-02-28

Abstract: Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone1. However, there remains little consensus on the mechanism(s) of response with this combination2. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8+ T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development.

DOI: 10.1038/s41586-024-07121-9

Source: https://www.nature.com/articles/s41586-024-07121-9