In recent years, broader localization of JMJD6 was detected including the nucleus, cytoplasm, and extracellular matrix, and its target proteins including histones, non-histones p53 and protein associated with RNA-splicing. JMJD6 was initially conceived as a phosphatidylserine receptor (PSR, Ptdsr) expressed on the surface of macrophages, mediating the phagocytosis of apoptotic cells. JMJD6 regulates the level of medullary thymic epithelial cell (mTEC) mature proteins via its ability to induce intron retention and the release of the Aire gene, which is required for self-immunity in the thymus. Moreover, with its arginine demethylation activities, JMJD6 is involved in multi-organ autoimmunity, modulating immune pathways such as Toll-like receptor related signal transduction. For instance, JMJD6 has been identified as a predicting marker for tumor response to tamoxifen endocrine therapy in breast cancer patients. The tumor expression of JMJD6 was also correlated with treatment resistance. The aberrant expression of JMJD6 has been reported in a wide panel of tumor types such as breast, hepatic, prostate cancer, colorectal cancer and neuroblastoma. The present study for the first time identified JMJD6 (Jumonji domain-containing 6) as a novel regulator of TAM activation which would serve as a therapeutic target and combination partner for ICBs in cancer. On the other hand, despite numerous efforts, the molecular mechanism of TAMs polarization remains incompletely defined. It is thus intriguing to speculate whether the therapeutic targeting of TAMs could revert the suppressive TME by blocking the immunosuppressive activities of TAMs. TAM infiltration in some cases may induce immunosuppression by reshaping the immune microenvironment through the inhibition of the cytotoxic T lymphocyte (CTL) response. Substantial evidence suggests the protumoral effect of TAMs such as the promotion of tumor growth, angiogenesis, matrix remodeling, and tumor cell invasion and motility. TAMs are often characterized with the gene expression profile of M2 macrophages, such as the surface markers CD163, CD206 and Arg1, and the secretory factors IL-10 and TGF-β. The tumor-associated macrophage (TAM) is the most abundant group of immune cells in the TME, which plays a critical role in the regulation of tumor progression and treatment resistance. Tumors are not simple stacks of malignant cells, but a complex system involving the tumor microenvironment (TME) including the extracellular matrix, vascular system and immune cells. These findings highlight the regulatory activities of JMJD6 in TAM polarization, and the therapeutic potential of JMJD6/STAT3/IL-10 axis blockades to enhance the efficacy of ICBs in cancer treatment. Moreover, the JMJD6-induced inhibition of M2 polarization was potentially mediated by the STAT3/IL-10 signaling. JMJD6 deficiency attenuated the growth of both Lewis lung carcinoma (LLC) tumors and B16F10 melanomas by reversing M2-like activation of macrophages, and sensitized tumors to immune checkpoint blockades (ICBs). The present study identified JMJD6 (Jumonji domain-containing 6) as a novel modulator of TAM activation, the upregulation of which was associated with the immunosuppressive activities of TAMs. Based on different polarization status, TAMs may also induce antitumor immune responses or immunosuppression. The tumor-associated macrophage (TAM) is the most abundant group of immune cells in the tumor microenvironment (TME), which plays a critical role in the regulation of tumor progression and treatment resistance.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |