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Beclin-1 as a neutrophil-specific immune checkpoint
Yu-Lin Su, Marcin Kortylewski
Yu-Lin Su, Marcin Kortylewski
Published October 28, 2019
Citation Information: J Clin Invest. 2019;129(12):5079-5081. https://doi.org/10.1172/JCI132534.
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Commentary

Beclin-1 as a neutrophil-specific immune checkpoint

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Abstract

Neutrophils are early wound healing and inflammation regulators that, due to functional plasticity, can adopt either pro- or antitumor functions. Until recently, beclin-1 was a protein known mainly for its role as a critical regulator of autophagy. In this issue of the JCI, Tan et al. describe the effects of the beclin-1 conditional myeloid cell–specific deletion in mice, in which immunostimulation resulted in hypersensitive neutrophils. The chronic proinflammatory effect of these neutrophils triggered spontaneous B cell malignancies to develop. Such tumorigenic effects were mediated primarily by IL-21 and CD40 signaling, leading to the upregulation of tolerogenic molecules, such as IL-10 and PD-L1. The authors went on to examine samples derived from patient lymphoid malignancies and showed that beclin-1 expression in neutrophils positively correlated with pre–B cell leukemia/lymphoma. Overall, the study provides an elegant model for neutrophil-driven carcinogenesis and identifies potential targets for immunotherapy of B cell malignancies.

Authors

Yu-Lin Su, Marcin Kortylewski

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Figure 1

Beclin-1 operates as an immune checkpoint regulator in neutrophils.

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Beclin-1 operates as an immune checkpoint regulator in neutrophils.
A mo...
A model for the interaction between Becn1-deficient neutrophils and B cells or B cell leukemia/lymphoma cells in vivo shows beclin-1 deficiency unleashes inflammatory TLR signaling in neutrophils by stabilizing MEKK3, leading in turn to excessive p38 signaling. As a result, hyperactive neutrophils initiate CXCR3/CXCL9-mediated B cell chemotaxis. The release of proinflammatory mediators, such as IL-21, and the expression of CD40 ligand by neutrophils triggers MAPK and Jak/STAT signaling in B cells, resulting in the production of immunosuppressive regulators IL-10 and PD-L1. These tolerogenic effects likely contribute to the development of B cell ALL.
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