Leveraging TNFR2 for antitumour immunity: T reg depletion and myeloid reprogramming versus T cell costimulation

Abstract Although checkpoint inhibitors have revolutionized cancer treatment, responses are largely restricted to targeting CTLA-4 and PD-(L)1. TNFR2 has been identified as a target of interest, but a lack of understanding of whether agonists or blockers should be used, and whether FcγR interactions promote effcacy, has hampered therapeutic antibody development. Here, we engineered two distinct α-TNFR2 types: ligand-blocking FcγR-engaging versus non-ligand-blocking agonist antibodies. Both showed potent anti-tumor effcacy across multiple syngeneic mouse tumor models and combined effectively with α-PD-1. The ligand-blocking antibody depleted intratumoral T regs and reprogrammed the myeloid compartment, directing monocytes towards a pro-inflammatory macrophage and dendritic cell trajectory. Surprisingly, this effect depended on both inhibitory and activating FcγRs. In contrast, the agonist directly co-stimulated T and NK cells, through partially FcγR-independent mechanisms. Both antibodies converged on activating tumor-specific CD8 + T cells mediating tumor rejection. Clinical assessment of both ligand-blocking (BI-1808) and agonist (BI-1910) α-TNFR2 antibodies is currently ongoing. Graphical abstract Ligand-blocking anti-TNFR2 mAbs (BI-1808 and 3F10) deplete CCR8 + T regs and activate myeloid cells, remodeling the TME and leading to CD8 + T cell killing of cancer cells. T reg depletion and myeloid activation are mediated through interaction with activating FcγRs and the inhibitory FcγRIIB, respectively. Agonist anti-TNFR2 mAbs (BI-1910 and 5A05) intrinsically agonize TNFR2 on T cells and NK cells, which is enhanced by FcγRIIB crosslinking. The resulting broad lymphocyte activation mediates cancer cell killing.