Science

Aug 17, 2025, 07:26

Himanshu Mishra: DNASE1L3-Driven NET Degradation Boosts Immunotherapy Efficacy

Himanshu Mishra, Microbiologist At Zydus Lifescience pvt Ltd Ahemdabad, shared a post on LinkedIn:

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

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.

Highlights:

DNASE1L3+ dendritic cells predict better immunotherapy outcomes in cancer patients.
DNASE1L3 loss in dendritic cells drives tumor growth via CD8+ T cell dysfunction.
DNASE1L3+ dendritic cells maintain cytotoxic CD8+ T cell hubs by degrading NETs.
Exogenous DNASE1L3 treatment enhances anti-PD-L1 therapy efficacy.”

Himanshu Mishra: DNASE1L3-Driven NET Degradation Boosts Immunotherapy Efficacy