Myeloid loss of Beclin 1 promotes PD-L1hi precursor B cell lymphoma development
Peng Tan, … , Helen Y. Wang, Rong-Fu Wang
Peng Tan, … , Helen Y. Wang, Rong-Fu Wang
Published September 10, 2019
Citation Information: J Clin Invest. 2019;129(12):5261-5277. https://doi.org/10.1172/JCI127721.
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Research Article Immunology Oncology

Myeloid loss of Beclin 1 promotes PD-L1hi precursor B cell lymphoma development

Abstract

Beclin 1 (Becn1) is a key molecule in the autophagy pathway and has been implicated in cancer development. Due to the embryonic lethality of homozygous Becn1-deficient mice, the precise mechanisms and cell type–specific roles of Becn1 in regulating inflammation and cancer immunity remain elusive. Here, we report that myeloid-deficient Becn1 (Becn1ΔM) mice developed neutrophilia, were hypersusceptible to LPS-induced septic shock, and had a high risk of developing spontaneous precursor B cell (pre-B cell) lymphoma with elevated expression of immunosuppressive molecules programmed death ligand 1 (PD-L1) and IL-10. Becn1 deficiency resulted in the stabilization of MEKK3 and aberrant p38 activation in neutrophils, and mediated neutrophil–B cell interaction through Cxcl9/Cxcr3 chemotaxis. Neutrophil–B cell interplay further led to the activation of IL-21/STAT3/IRF1 and CD40L/ERK signaling and PD-L1 expression; therefore, it suppressed CD8+ T cell function. Ablation of p38 in Becn1ΔM mice prevented neutrophil inflammation and B cell tumorigenesis. Importantly, the low expression of Becn1 in human neutrophils was significantly correlated with the PD-L1 levels in pre-B acute lymphoblastic lymphoma (ALL) patients. Our findings have identified myeloid Becn1 as a key regulator of cancer immunity and therapeutic target for pre-B cell lymphomas.

Authors

Peng Tan, Lian He, Changsheng Xing, Jingrong Mao, Xiao Yu, Motao Zhu, Lixia Diao, Leng Han, Yubin Zhou, M. James You, Helen Y. Wang, Rong-Fu Wang

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Figure 2

Cell type–specific regulation of Becn1 in proinflammatory signaling pathways and immune responses.

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Cell type–specific regulation of Becn1 in proinflammatory signaling path...
(A and B) Neu (A) or pMAC (B) from the periphery of WT and Becn1ΔM mice were treated with LPS for the indicated time points, followed by IB with indicated antibodies. (C) ELISA measurement of TNF-α, IL-6, and IL-1β production by Neu and pMAC of WT and Becn1ΔM mice treated with 100 ng/ml LPS for indicated time points (n = 4). (D) IB of pro–IL-1β expression in Neu or pMAC from WT and Becn1ΔM mice. (E) Survival of WT and Becn1ΔM mice (n = 10; female) treated with high-dose LPS (30 mg/kg, i.p.). (F) Plasma concentrations of TNF-α, IL-6, and IL-1β in WT or Becn1ΔM mice (n = 5) at indicated time points after LPS treatment. (G) Survival of WT and Becn1ΔM mice (n = 4; female) treated with PBS- or clodronate-containing liposomes to deplete macrophages or with anti-Ly6G antibody (1A8) to deplete neutrophils, followed by high-dose LPS treatment. (H) Heatmap representation of differential expressed genes in neutrophils isolated from Becn1ΔM mice compared with WT controls: neutrophil-mediated immunity and IL-17–related cytokines (purple), chemokine receptor and neutrophil-chemotaxis (green), cell metabolism (blue). Data shown in A, B, and D are representative of 3 independent experiments with 6- to 8-week-old mice (n = 3; female) in each group. Statistical differences between groups were calculated using Student’s unpaired t test (mean ± SEM) (C and F) and Mantel-Cox log-rank test (E and G). *P < 0.05; **P < 0.01; ***P < 0.001.