Guan, X., Hu, R., Choi, Y., Srivats, S., Nabet, B. Y., Silva, J., McGinnis, L., Hendricks, R., Nutsch, K., Banta, K. L., Duong, E., Dunkle, A., Chang, P. S., Han, C., Mittman, S., Molden, N., Daggumati, P., Connolly, W., Johnson, M., . . . Patil, N. S. (2024). Anti-TIGIT antibody improves PD-L1 blockade through myeloid and Treg cells. Nature, 627(8004), 646–655. https://doi.org/10.1038/s41586-024-07121-9
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 fnd 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 beneft in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies infamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8+
T cells from an exhausted efector-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.
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