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

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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