Beclin-1 as a neutrophil-specific immune checkpoint

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Neutrophils are key regulators of inflammation and wound healing, with a functional plasticity that allows them to influence antitumor responses.
• Beclin-1, a protein primarily known for its role in autophagy, has emerging functions in immune regulation and cancer.
• The role of beclin-1 in neutrophil function and its potential impact on carcinogenesis remained largely unexplored.

Purpose of the Study:

• To investigate the role of beclin-1 in myeloid cells, specifically neutrophils, in the context of immune responses and cancer development.
• To elucidate the mechanisms by which beclin-1 deficiency in neutrophils might contribute to tumorigenesis.
• To explore the translational relevance of these findings in human lymphoid malignancies.

Main Methods:

• Generation of mice with a conditional myeloid cell-specific deletion of beclin-1.
• Immunostimulation of these mice to assess neutrophil function and inflammatory responses.
• Analysis of B cell malignancies, cytokine signaling (IL-21, IL-10), cell surface markers (CD40, PD-L1), and patient samples.

Main Results:

• Conditional deletion of beclin-1 in myeloid cells led to hypersensitive neutrophils with a chronic proinflammatory phenotype.
• These neutrophils promoted spontaneous B cell malignancies through IL-21 and CD40 signaling, upregulating tolerogenic molecules like IL-10 and PD-L1.
• Beclin-1 expression in neutrophils positively correlated with pre-B cell leukemia/lymphoma in patient samples.

Conclusions:

• Beclin-1 is crucial for regulating neutrophil function and preventing chronic inflammation that can drive carcinogenesis.
• Neutrophil-driven carcinogenesis, mediated by specific signaling pathways, represents a novel mechanism in B cell malignancies.
• Beclin-1 in neutrophils is a potential biomarker and therapeutic target for B cell malignancies.