Regulation of tumor-related macrophages on the development of glioma

Tumor-related macrophages (tumor-associated macrophages, TAM) play an important role in the immune response of tumors, but it is not clear how TAM and T cells regulate immune function in tumor microenvironmentsin glioblastoma (glioblastoma, GBM), the presence of tam intermediate phenotypes with M1/M2 type, M2-type TAM-like, is associated with tumor progression and immunofunctional inhibition, suggesting that TAM transcription regulation may be involved in the pathological process of tumor developmentexperiments designing glioma exosocyllal cells and tumor animal models, such as Maisa CTakenaka of Harvard Medical School and Women's Hospital, to study the immunomotoregulatory mechanisms of TAM and T-cells in tumor microenvironments, the results of which were published in the May 2019 issue of Nature Neurosciencethe studythe authors used mouse GL261 glioma cells to produce tumor condition medium (tumor-conditioned media, TCM) and study the effects of TCM on rat macrophagesIt was found that The M1 type (stat1, cd274, Il1b, Tnfa and Il27) and M2 (Arg1, Vegfa, Il10, Klf4 and Pparg) markers in the TCM upward spleen macrophage were raisedA recent study of GBM secretes kynurm (kynurnine, KYN), activating the downstream pathway of the aromatic hydrocarbon receptor (aryl hydrocarbon receptor, AHR) to promote the development of GBMFurther analysis of the effects of TCM on AHR expression and TAM activation found that its expression significantly improved, indicating that AHR increased positive macrophages or was raised by GBMthe resultsstat1 and STAT3 expression increased in the cyaphage and GBM specimens after TCM treatment, and their corresponding inhibitors inhibited the expression of AHRThe bio-letter analysis found that there are binding sites of miR-29a and miR-29b in 3'UTR of the AHR gene siteExperimental studies have shown that expression miR-29b inhibits AHR expressionThe above experimental results suggest that the expression of AHR in TAM is subject to positive regulation of STAT1 and STAT3, and negative regulation of miR-29bin AHR
LysMmouse model, after implanting GL261 glioma cells, tumor growth slowed and mice survived longer GBM tumor cells recruit TAM by secreting CCL2 After knocking out AHR or inhibiting its function, the migration of macrophages under the CCL2 concentration gradient was significantly inhibited In intracranial transplanted AHR LysM mouse spleen macrophages and GL261 glioma cell TAM, cCL2 receptor CCR2 expression decreased It shows that AHR plays an important role in THE GBM recruitment process mice lacking in AHR led to a decrease in the expression of M2-type macrophages-related genes, while an increase in m1-type macrophages-related gene expression suggested that AHR played an important role in TAM polarization TCM medium and KYN rely on AHR to activate Klf4 promoters (Klf4 is known to drive M2 gene expression in peripheral macrophages), and Klf4 knock-out leads to inhibition of M2-related genes Arg1, Mrc1 and Clec10a In addition, AHR can inhibit the NF-B signaling pathway by promoting SOCS2 expression and TRAF6 degradation, thereby acting as an immunosuppressor and promoting tumor growth The above experiments confirmed that KYN is regulated by AHR for immunity, etc TCM medium and KYN can also activate the Entpd1 promoter by AHR dependence, promoting the expression of the external nucleotide enzyme CD39 CD39 and CD73 work together to promote the production of nucleotide adenosine by TAM, further leading to CD8 and tumors inlaticity of lymphocytes, promoting the immunity of tumor escape TCGA database analysis also confirmed that AHR, CYP1A1 and STAT1 were independent factors of poor prognosis in GBM patients conclusions , the authors confirm the important role of AHR in the immune microenvironment of GBM tumors, and explain its upstream and downstream regulatory mechanisms: AHR can regulate the expression of CD39, resulting in CD8-T cell dysfunction At the same time, High AHR expression was significantly associated with poor prognosis in GBM patients.