a-TIGIT mAb belrestotug in combination with anti-PD1 induces an immunocompetent tumor microenvironment (TME)

Abstract Belrestotug, a monoclonal antibody against TIGIT, was evaluated alone and with anti-PD-1 therapy in two clinical trials for advanced solid cancers ( NCT04335253 , NCT05060432 ). Belrestotug alone reduced Treg cells and transiently increased proliferating T/NK cells, indicating immune activation in the periphery. Combined with anti-PD-1, it promoted earlier T cell proliferation and further decreased Treg numbers both in blood and tumors, potentially overcoming Treg-related resistance to PD-1 blockade. Spatial analysis demonstrated a reduction of TIGIT+ regulatory T cells within the tumor, along with increased CD8 IFNγ expression and macrophage-associated signatures. These findings indicate that this combination therapy may enhance anti-tumor immune responses by depleting immunosuppressive Tregs and remodeling the tumor microenvironment. Several studies proposed that PD-(L)-1 blockade responses occur mostly in patients with inflamed immunotype, where an enriched immune infiltrate distributes both in tumor nest and stroma regions. Conversely, in excluded immunotypes the immune infiltrate is preferentially localized in the stroma. Our data in late-stage patients, mixed solid tumors, supports that the combination therapy remodels immune cells distribution in the stroma, potentially indicating that inflamed and excluded immunotypes may be predictive biomarkers of response for belrestotug combination with aPD1.