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 December 2, 2019; First published September 10, 2019
Citation Information: J Clin Invest. 2019;129(12):5261-5277. https://doi.org/10.1172/JCI127721.
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Categories: 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, James M. You, Helen Y. Wang, Rong-Fu Wang

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Figure 3

Becn1 ablation suppresses proteasomal degradation of neutrophil MEKK3 upstream of p38.

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Becn1 ablation suppresses proteasomal degradation of neutrophil MEKK3 u...
(A and B) Screening of Becn1 binding proteins in NF-κB and MAPK pathways in 293T cells. WCL, whole-cell lysate. (C) 293T cells transfected with 100 ng HA-MEKK3 along with increased amounts (0, 100, 250, and 500 ng) of FLAG-Becn1, followed by IB with indicated antibodies. (D) IB of MEKK3 protein expression in Becn1-deficient Neu and pMAC compared with WT controls. (E and F) WT or Becn1-deficient neutrophils were treated with LPS for the indicated time points, followed by IB with antibodies against MEKK3, TAK1 or p-p38 (E), and MKK3/6 signaling (F). (G) IB of 293T cells transfected with HA-MEKK3 along with empty vector or FLAG-Becn1 left untreated or treated with proteasome inhibitor MG132 (1 μM) or autophagy inhibitors 3-MA (5 mM) or CQ (10 μM). (H) IB of 293T cells transfected with WT or HA-MEKK3 (K69R, K79R, K174R, K273R, K299R, K397R, K435R) along with empty vector or FLAG-Becn1. (I) 293T cells were transfected with FLAG-MEKK3 WT or FLAG-MEKK3 K299R along with GFP-Becn1 and HA-ubiquitin K48 expression vectors, followed by immunoprecipitation with FLAG beads and IB with indicated antibodies. Data are representative of 3 independent experiments in 293T cells (A–C and G–I) and with 6- to 8-week old mice (n = 3; female) (D–F).