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

Characterization and phenotypic analysis of Becn1ΔM mice.

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Characterization and phenotypic analysis of Becn1ΔM mice. (A) SP size co...
(A) SP size comparison between WT and Becn1ΔM mice and SP/ body weight ratio (n = 4). H&E staining of SP sections from WT and Becn1ΔM mice. Scale bars: 500 μm. (B) Lymphadenopathy in Becn1ΔM mice compared with WT control. Inguinal (i), axillary (ii), and mesenteric (iii) LNs were examined. Data are representative of 3 independent experiments with 6- to 8-week-old mice (n = 2) in each group. (C) Total number of splenic CD45+CD11c+ DCs, CD4+ T cells, CD8+ T cells, B220+ B cells, CD11b+F4/80+ macrophages, and CD11b+Ly6G+ neutrophils from WT and Becn1ΔM mice (n = 4). (D and E) Representative flow cytometry plots and statistical analysis of Gr-1+CD11b+ myeloid cells, Ly6G+CD11b+ neutrophils, and F4/80+CD11b+ macrophages in BM (D) and SP (E) of WT and Becn1ΔM mice (n = 5). (F and G) Representative flow cytometry plots and statistical analysis of monocytic (Ly6ChiLy6G–) and granulocytic (Ly6CintLy6G+) cells in BM (F) and SP (G) of 6-to 8-week-old WT and Becn1ΔM mice (n = 5). Data represented in A and C–G were from 6- to 8-week-old mice and are presented as box plots, with lines representing median and error bars showing mean ± SEM. Statistical differences between groups were calculated using Student’s unpaired t test. *P < 0.05; **P < 0.01.