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.
View: Text | PDF
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

×

Figure 6

Becn1 deficiency induces B cell helper protumorigenic function of neutrophils.

Options: View larger image (or click on image) Download as PowerPoint
Becn1 deficiency induces B cell helper protumorigenic function of neutr...
(A and B) IHC staining or IF of tumor in cLN and lung stained with indicated antibody showing the interaction of B cells with neutrophils (arrows). DAPI, DNA-intercalating dye (nucleus, blue). Scale bars: 25 μm. (C) IHC staining of intestinal Peyer’s patch sections with indicated antibodies (green circle indicates B cell zone; arrowheads indicate neutrophils). Scale bars: 500 μm. Drawing illustrates a strip of neutrophils surrounding the edge of the B cell zone likely to support B cell proliferation and migration. (D) qRT-PCR of B cell helper neutrophil signature genes. (E) ELISA analysis of BAFF and IL-21 production by neutrophils after in vitro culture for 12 hours. IF shows accumulation of Gr-1+CD11b+ neutrophils in the tumor expressing IL-21. Original magnification, ×20. (F) IB of p38 activation in neutrophils from lymphoma (T) and lungs in Becn1ΔM tumor-bearing mice compared with WT controls. N, normal. (G) Fluorescence and statistical analysis of NET formation in neutrophils using SYTOX dye (green). White arrows indicate NETs. Scale bars: 100 μm. (H) IF of tumor section with Ly6G (red) and CXCR3 (green) antibodies compared with WT LN. Scale bars: 25 μm. (I) IHC staining of tumor sections with anti-CXCL9 antibody compared with WT LN. Scale bars: 200 μm. Data are presented as box plots with error bars showing mean ± SEM (D, E, and G) and are representative of 3 independent experiments (n = 3; female) (A–C, F, H, and I). Statistical differences between groups were calculated using 1-way ANOVA with Dunnett’s multiple comparison test (D and E) and Student’s unpaired t test (G). *P < 0.05; **P < 0.01.