BATF2 prevents glioblastoma multiforme progression by inhibiting recruitment of myeloid-derived suppressor cells

Abstract

The basic leucine zipper ATF-like transcription factor 2 (BATF2) has been implicated in inflammatory responses and anti-tumour effects. Little, however, is known regarding its extracellular role in maintaining a non-supportive cancer microenvironment. Here, we show that BATF2 inhibits glioma growth and myeloid-derived suppressor cells (MDSCs) recruitment. Interestingly, extracellular vesicles (EVs) from BATF2-overexpressing glioma cell lines (BATF2-EVs) inhibited MDSCs chemotaxis in vitro. Moreover, BATF2 inhibited intracellular SDF-1α and contributes to decreased SDF-1α in EVs. In addition, BATF2 downregulation-induced MDSCs recruitment were reversed by blocking SDF-1α/CXCR4 signalling upon AMD3100 treatment. Specifically, detection of EVs in 24 pairs of gliomas and healthy donors at different stages revealed that the abundance of BATF2-positive EVs in plasma (BATF2+ plEVs) can distinguish stage III–IV glioma from stage I–II glioma and healthy donors. Taken together, our study identified novel regulatory functions of BATF2 in regulating MDSCs recruitment, providing a prognostic value in terms of the number of BATF2+ plEVs in glioma stage.

Blood RNA Sequencing Indicates Upregulated BATF2 and LY6E and Downregulated ISG15 and MT2A Expression in Children with Autism Spectrum Disorder

“…The protein coded by BATF2 was shown to have an antitumor effect in a mouse model through upregulation of IL-12 p40 in tumor-associated macrophages, leading to CD8 + T-cell activation and tumor accumulation [ 27 ]. Among other cancers, BATF2 was demonstrated as a tumor suppressor of gastric cancer [ 28 ], glioblastoma [ 29 ], and esophageal squamous cell carcinoma [ 30 ]. In contrast, LY6E , the other gene found as upregulated in ASD blood samples, was suggested as a biomarker of poor prognosis in smoking-induced lung carcinogenesis [ 31 ] and colorectal cancer [ 32 ].…”

In Situ Deployment of Engineered Extracellular Vesicles into the Tumor Niche via Myeloid‐Derived Suppressor Cells

“…[46,47] Although this is clearly an important issue meriting further study, there is evidence that MDSCs can traffic to brain tissue in certain malignancies or in other neurodegenerative conditions. [48][49][50][51][52][53][54] Thus, the use of MDSCs as a platform technology for EV deployment may still be feasible for some applications where biological barriers are present.…”

Extracellular‐Vesicle‐Based Drug Delivery Systems for Enhanced Antitumor Therapies through Modulating the Cancer‐Immunity Cycle

“…[ 202 ] However, EVs from basis leucine zipper ATF‐like transcription factor 2‐overexpressing glioma cells restricted MDSC recruitment, contributing to glioma inhibition. [ 203 ] PD‐1‐overexpressed platelet‐derived MPs from genetically modified megakaryocytes were loaded with cyclophosphamide to deplete Tregs, resulting in the increased proportion of re‐activated CD8 + T cells in the post‐surgical tumor microenvironment to inhibit tumor recurrence. [ 120 ] In addition, antimetastatic and antitumoral genes tissue inhibitors of metalloproteases‐3 ( Timp3)‐ and retinoic acid receptor 2 ( Rarres2)‐ transfected MDSCs showed tumor homing ability, and released Timp3 ‐ or Rarres2 ‐overexpressing EVs at tumor tissues to elicit anticancer immune responses in situ.…”