Abstract

Abstract Tiragolumab, an anti-TIGIT antibody with an active IgG1/kappa Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone. To understand the mechanism(s) of response with this combination, we leveraged tumor pretreatment samples, and peripheral blood mononuclear cells (PBMC) and serum samples (baseline and on-treatment) collected from patients enrolled in the clinical trials, as well as the syngeneic CT26 mouse tumor model by using mouse tiragolumab surrogate antibodies. Bulk RNA-seq, proteomics, scSeq, and flow cytometry were performed. We found that high baseline intratumoral macrophages and Tregs were associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Comparing the on-treatment versus baseline serum samples revealed that macrophage activation was associated with clinical benefit in patients receiving the combination treatment. In mouse tumor models, tiragolumab surrogate antibodies inflamed tumor-associated macrophages, monocytes, and dendritic cells through Fc gamma receptors (FcɣR), in turn driving anti-tumor CD8+ T cells from an exhausted effector-like state to a more memory-like one. These results uncover a mechanism of action by which TIGIT checkpoint inhibitors can remodel immunosuppressive tumor microenvironments, and suggest that FcɣR engagement is an important consideration in anti-TIGIT antibody development.

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