1. Myeloid loss of Beclin 1 promotes PD-[L1.sup.hi] precursor B cell lymphoma development
- Author
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Tan, Peng, He, Lian, Xing, Changsheng, Mao, Jingrong, Yu, Xiao, Zhu, Motao, Diao, Lixia, Han, Leng, Zhou, Yubin, You, James M., Wang, Helen Y., and Wang, Rong-Fu
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Thermo Fisher Scientific Inc. ,Scientific equipment and supplies industry ,T cells ,Inflammation -- Development and progression ,Non-Hodgkin's lymphomas -- Development and progression ,B cells ,Septic shock -- Development and progression ,Health care industry - 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 ([Becn1.sup.[DELTA]M]) 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.sup.+] T cell function. Ablation of p38 in [Becn1.sup.[DELTA]M] 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., Introduction Autophagy has been well recognized as a key intracellular degradation and recycling machinery for maintaining cellular homeostasis, whose dysregulation leads to cancer (1). Beclin 1 (Becn1) acts as a [...]
- Published
- 2019
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