Batf3+ DCs and the 4-1BB/4-1BBL axis are required at the effector phase in the tumor microenvironment for PD-1/PD-L1 blockade efficacy

The cellular source of positive signals that reinvigorate T cells within the tumor microenvironment (TME) for the therapeutic efficacy of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade has not been clearly defined. We now show that Batf3-lineage dendritic cells (DCs) are essential in this process. Flow cytometric analysis, gene-targeted mice, and blocking antibody studies revealed that 4-1BBL is a major positive co-stimulatory signal provided by these DCs within the TME that translates to CD8+ T cell functional reinvigoration and tumor regression. Immunofluorescence and spatial transcriptomics on human tumor samples revealed clustering of Batf3+ DCs and CD8+ T cells, which correlates with anti-PD-1 efficacy. In addition, proximity to Batf3+ DCs within the TME is associated with CD8+ T cell transcriptional states linked to anti-PD-1 response. Our results demonstrate that Batf3+ DCs within the TME are critical for PD-1/PD-L1 blockade efficacy and indicate a major role for the 4-1BB/4-1BB ligand (4-1BBL) axis during this process. [Display omitted] •DC1s are needed in the TME for PD-1/PD-L1 blockade efficacy•Anti-PD-L1-induced CD8+ T cell reinvigoration in the TME is 4-1BB/4-1BBL dependent•DC1/CD8+ T cell clustering is associated with clinical response to PD-1 blockade•CD8+ T cell proximity to DC1 is associated with transcriptomics linked to treatment response Ziblat et al. demonstrate that Batf3+ dendritic cells (DC1s) are needed within the tumor for efficacy of PD-1/PD-L1 blockade. Mechanistically, they show that DC1s deliver positive signals through 4-1BB/4-1BBL for the reinvigoration of CD8+ T cells once PD-1/PD-L1 is blocked and that DC1-CD8 clustering correlates with anti-PD-1 clinical efficacy.