| First Author | Tan P | Year | 2019 |
| Journal | J Clin Invest | Volume | 129 |
| Issue | 12 | Pages | 5261-5277 |
| PubMed ID | 31503548 | Mgi Jnum | J:283322 |
| Mgi Id | MGI:6387586 | Doi | 10.1172/JCI127721 |
| Citation | Tan P, et al. (2019) Myeloid loss of Beclin 1 promotes PD-L1hi precursor B cell lymphoma development. J Clin Invest 129(12):5261-5277 |
| abstractText | 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 (Becn1DeltaM) 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 Becn1DeltaM 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. |
