Itai et al. analyzed the effects of anti-PD-1 on CD8+ T cells in tumor-bearing mice (inducibly) depleted of cDC1s, and showed that PD-1+ CD8+ T cell/XCR1+ cDC1 TME interactions impacted antitumor responses and anti-PD-1 efficacy. A non-Fc-binding PD-1/CLEC9A bispecific antibody (BiCE) was generated and shown to induce transient PD-1+ T cell/migratory cDC1 conjugates, leading to cDC1 maturation and activation/proliferation of cytotoxic CD8+ T cells in the TME and TDLNs. In aggressive mouse tumor models, BiCE treatment was efficacious alone or with anti-CD40, had abscopal effects, inhibited metastases, and induced a TME milieu distinct from that resulting from standard ICB.
Contributed by Paula Hochman
ABSTRACT: Immune checkpoint inhibition treatment using aPD-1 monoclonal antibodies is a promising cancer immunotherapy approach. However, its effect on tumor immunity is narrow, as most patients do not respond to the treatment or suffer from recurrence. We show that the crosstalk between conventional type I dendritic cells (cDC1) and T cells is essential for an effective aPD-1-mediated anti-tumor response. Accordingly, we developed a bispecific DC-T cell engager (BiCE), a reagent that facilitates physical interactions between PD-1(+) T cells and cDC1. BiCE treatment promotes the formation of active dendritic/T cell crosstalk in the tumor and tumor-draining lymph nodes. In vivo, single-cell and physical interacting cell analysis demonstrates the distinct and superior immune reprogramming of the tumors and tumor-draining lymph nodes treated with BiCE as compared to conventional aPD-1 treatment. By bridging immune cells, BiCE potentiates cell circuits and communication pathways needed for effective anti-tumor immunity.