Genentech Inc., South San Francisco, CA, USA.
Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA.
Nature. 2024 Mar;627(8004):646-655. doi: 10.1038/s41586-024-07121-9. Epub 2024 Feb 28.
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 alone. However, there remains little consensus on the mechanism(s) of response with this combination. 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.
替雷利珠单抗是一种抗 TIGIT 的抗体，具有活性 IgG1κ Fc，与单独使用阿替利珠单抗（抗 PD-L1）相比，在 2 期 CITYSCAPE 试验（ClinicalTrials.gov：NCT03563716）中显示出改善的结果。然而，对于这种组合的反应机制仍存在较少共识。在这里，我们发现基线时肿瘤内巨噬细胞和调节性 T 细胞数量较高与接受阿替利珠单抗加替雷利珠单抗治疗的患者的更好结局相关，但与单独接受阿替利珠单抗治疗的患者无关。血清样本分析显示，在接受联合治疗的患者中，巨噬细胞的激活与临床获益相关。在小鼠肿瘤模型中，替雷利珠单抗替代抗体通过 Fcγ 受体（FcγR）使肿瘤相关巨噬细胞、单核细胞和树突状细胞炎症化，进而将耗竭效应样状态的抗肿瘤 CD8 T 细胞驱动到更类似于记忆的状态。这些结果揭示了 TIGIT 检查点抑制剂可以重塑免疫抑制性肿瘤微环境的作用机制，并表明 FcγR 结合是抗 TIGIT 抗体开发中的一个重要考虑因素。
