DNASE1L3-expressing dendritic cells promote CD8+ T cell function and anti-PD-(L)1 therapy efficacy by degrading neutrophil extracellular traps

Abstract

CD8⁺ T cell exclusion and dysfunction in the tumor microenvironment (TME) are among the most challenging obstacles for anti-PD-(L)1 therapy. Here, we report that tumor-infiltrating dendritic cell (DC)-specific expression of the deoxyribonuclease, DNASE1L3, is positively correlated with favorable outcomes of anti-PD-(L)1 treatment in cancer patients. DNASE1L3 conditional knockout in DCs leads to enhanced tumor growth and diminishes anti-PD-L1 therapeutic efficacy by impairing infiltration and effector functions of CD8⁺ T cells. Conversely, injection with DNASE1L3 promotes CD8⁺ T cell infiltration and reduces exhaustion in the TME, significantly retarding tumor growth and enhancing anti-PD-L1 response. DNASE1L3⁺ DCs can degrade neutrophil extracellular traps that suppress the spatial distribution of CD8⁺ T cells in tumors, enabling establishment of cytotoxic CD8⁺ T cell hubs in human cancers. Our findings reveal a role of DC in regulating intratumoral CD8⁺ T cells and identify DNASE1L3 as a promising target to improve anti-PD-(L)1 therapy.

Keywords: CD8(+) T cell; DNASE1L3; anti-PD-1/PD-L1 therapy; cellular community; dendritic cell; immune hubs; neutrophil extracellular traps.