Q1 · CROSS-FIELD
Article
Author: Felip, Enriqueta ; Duong, Ellen ; Hendricks, Robert ; Molden, Nandini ; Mellman, Ira ; Han, Chia-Jung ; Mittman, Stephanie ; Silva, John ; Abreu, Delvys Rodriguez ; Johnston, Robert J ; Guan, Xiangnan ; Nabet, Barzin Y ; Daggumati, Pallavi ; Mariathasan, Sanjeev ; Choi, Yoonha ; Cho, Byoung Chul ; Meng, Raymond ; McGinnis, Lisa ; Srivats, Shyam ; Dunkle, Alexis ; Nutsch, Katherine ; Gil-Bazo, Ignacio ; Chiang, Eugene Y ; Banta, Karl L ; Chang, Patrick S ; Hu, Ruozhen ; Shames, David S ; Italiano, Antoine ; Connolly, Wendy ; Johnson, Melissa ; Patil, Namrata S
AbstractTiragolumab, 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.