T cell-engaging bispecific antibodies (T-BsAbs) have shown impressive clinical responses in patients with relapsed/refractory B-cell malignancies, although treatment failure remains a major clinical challenge. Growing evidence suggests that the complex interplay between immune cells and tumor cells is implicated in the mechanism of action, and thus, understanding immune regulatory mechanisms might provide a clue for improving the efficacy of T-BsAb therapy. Here, we investigated the functional impact of regulatory T (Treg) cells on anti-tumor immunity elicited by T-BsAb therapy. In the myeloma preclinical model, the activation and expansion of Treg cells in the bone marrow were observed in response to anti-BCMA T-BsAb therapy. T-BsAb triggered the generation of induced Treg cells from human conventional CD4 cells after co-culture with tumor cells. Moreover, T-BsAb directly activated freshly isolated circulating Treg cells, leading to IL-10 production and inhibition of T-BsAb-mediated CD8 T cell responses. The activation of Treg cells was also seen in myeloma patients-derived bone marrow samples after ex vivo treatment with T-BsAb, further supporting the impact of T-BsAb on Treg homeostasis. Importantly, transient ablation of Treg cells in combination with T-BsAb therapy dramatically improved effector lymphocyte activities and disease control in the preclinical myeloma model, leading to prolonged survival. Together, therapy-induced activation of Treg cells critically regulates antitumor immunity elicited by T-BsAb therapy, providing important implications for improving the efficacy.
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