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

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 Fc{gamma}R interactions promote effcacy, has hampered therapeutic antibody development. Here, we engineered two distinct -TNFR2 types: ligand-blocking Fc{gamma}R-engaging versus non-ligand-blocking agonist antibodies. Both showed potent anti-tumor effcacy across multiple syngeneic mouse tumor models and combined effectively with -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 Fc{gamma}Rs. In contrast, the agonist directly co-stimulated T and NK cells, through partially Fc{gamma}R-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) -TNFR2 antibodies is currently ongoing. Graphical abstractO_LILigand-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 Fc{gamma}Rs and the inhibitory Fc{gamma}RIIB, respectively. C_LIO_LIAgonist anti-TNFR2 mAbs (BI-1910 and 5A05) intrinsically agonize TNFR2 on T cells and NK cells, which is enhanced by Fc{gamma}RIIB crosslinking. The resulting broad lymphocyte activation mediates cancer cell killing. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/697572v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@3ecc17org.highwire.dtl.DTLVardef@c936a7org.highwire.dtl.DTLVardef@23189aorg.highwire.dtl.DTLVardef@243a05_HPS_FORMAT_FIGEXP M_FIG C_FIG