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

Area of Science:

• Immunology
• Cancer Biology
• Cellular Signaling

Background:

• The tumor microenvironment (TME) plays a critical role in cancer immunotherapy.
• The cellular sources of co-stimulatory signals that enhance T cell function within the TME are not fully understood.
• Programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade is a key cancer immunotherapy strategy.

Purpose of the Study:

• To identify the specific immune cells responsible for providing positive signals that enhance T cell function within the TME.
• To elucidate the mechanisms by which these cells contribute to the efficacy of PD-1/PD-L1 blockade therapy.
• To investigate the role of the 4-1BB/4-1BBL axis in anti-PD-1 therapy response.

Main Methods:

• Flow cytometry and gene-targeted mouse models were used to identify key cell populations.
• Blocking antibody studies were performed to assess the role of specific signaling pathways.
• Immunofluorescence and spatial transcriptomics were employed on human tumor samples to analyze cell-cell interactions and transcriptional states.

Main Results:

• Batf3-lineage dendritic cells (DCs) were identified as essential for reinvigorating T cells within the TME.
• These Batf3+ DCs provide 4-1BBL, a co-stimulatory signal crucial for CD8+ T cell functional reinvigoration and tumor regression.
• Clustering of Batf3+ DCs and CD8+ T cells in human tumors correlates with anti-PD-1 efficacy, and proximity to Batf3+ DCs is linked to T cell states associated with therapy response.

Conclusions:

• Batf3+ DCs are critical cellular sources of co-stimulatory signals within the TME that drive PD-1/PD-L1 blockade efficacy.
• The 4-1BB/4-1BBL axis plays a major role in mediating the therapeutic benefits of PD-1/PD-L1 blockade.
• Targeting the interaction between Batf3+ DCs and CD8+ T cells may represent a novel therapeutic strategy to enhance cancer immunotherapy.