Integrated genomic, transcriptomic, and epigenetic analyses identify a leukotriene synthesis-related M2 macrophage gene signature that predicts prognosis and treatment vulnerability in gliomas

Abstract

The pathological implications of tumor-associated macrophages in the glioma microenvironment have been highlighted, while there lacks a gene signature to characterize the functional status and clinical implications of these cells. Comprehensive bioinformatics approaches were employed to develop an M2 macrophage-associated gene signature at bulk-tumor and single-cell levels and explore immunological and metabolic features. Consequently, the PI3K pathway and fatty acid metabolism were correlated with the M2 fraction. Further distilling the pathway members resulted in a leukotriene synthesis-related gene signature (Macro index), including PIK3R5, PIK3R6, ALOX5, ALOX5AP, and ALOX15B, that was primarily expressed by monocytes/macrophages. Increased Macro index predicted IL13-induced macrophages, and was associated with T-cell dysfunction at both transcriptional and epigenetic levels and predicted an unfavorable outcome. Besides, the Macro index was proportional with PAI1 at the protein level, with high levels of the latter suggesting a decreased progression-free interval of glioblastoma. Notably, the monocytes/macrophages in the glioma environment contribute to the expression of immune checkpoints and the Macro index predicts glioma responsiveness to anti-PD1 treatment. Together, our study proposed a leukotriene synthesis-related M2 macrophage gene signature, which may provide insights into the role of these cells in the glioma microenvironment and facilitate individually tailored therapeutic strategies for the disease.

The mycosis fungoides cutaneous microenvironment shapes dysfunctional cell trafficking, antitumor immunity, matrix interactions, and angiogenesis

“…Recent reports indicated that accumulation of MDSCs may be crucial in CTCL progression ( 47 ), and Geskin et al observed a reduction in MDSC activity following IFNα2b therapy ( 48 ), suggesting a possible correlation with the effective treatment by IFN. The second MF-specific macrophage subset (APOE + TAMs) identified M2-like TAMs ( 49 ), upregulating MRC1 , CSF1R , CD81 , chemokines, matrix remodeling, cathepsins, complement, eicosanoid, and apolipoprotein genes, all contributing to promote immunosuppression, tumor cell extravasation, migration, survival, and proliferation ( 50 – 52 ). Our analysis also identified a subset of tumor-infiltrating pDCs in most of the MF samples that expressed TGFB1 , ICOSLG , and LILRA4 .…”

An engineered glioblastoma model yields novel macrophage-secreted drivers of invasion

“…Our findings begin to deconstruct complex TAM-GBM cell interactions and support ongoing therapeutic efforts aimed at repolarizing M2 macrophages towards M1-like polarization states, as well as offering novel therapeutic targets that could prevent the potent effects of M2 macrophages on GSCs. [53][54][55][56] While there have been reports of high M2 TAM accumulation in MES tumors, the mechanism behind this correlation remains unclear, although it has been proposed that MES tumors attract M2 TAMs. 8,57 Our work expands on prior studies investigating the relationship between TAM abundance and GBM subtype by proposing the possibility that M2 TAM secreted factors directly induce MES transition in tumor cells.…”

ALOX5 and ALOX5AP as an mRNA metric predicts unfavorable prognosis in lower-grade glioma

“…Despite the wellknown pro-tumoral role of prostaglandins, the pathological implication of leukotrienes remains less understood. Previous study has shown that alternative activated macrophages promote glioblastoma in a leukotriene dependent manner (9). Leukotrienes include the dihydroxy fatty acid leukotriene B4 (LTB 4 ) and cysteinyl-leukotrienes (LTC 4 , LTD 4 , LTE 4 ) (10,11).…”