The IgG Fc glycans strongly influence the Fcγ receptor interactions and Fc-mediated effector mechanisms. Changes in the structure of IgG glycans are associated with various diseases, such as infections and autoimmunity. However, the possible role of Fc glycans in tumor immunity is not yet fully understood. The aim of this study was to profile the Fc N-glycans of IgG samples from patients with gastric cancer (n = 80) and controls (n = 51) using LC-ESI-MS method to correlate the findings with stage of cancer and patients survival. Analysis of 32 different IgG N-glycans revealed significant increase of agalactosylated (GnGnF, GnGn(bi)F), and decrease of galactosylated (AGn(bi), AGn(bi)F, AA(bi), AAF) and monosialylated IgG glycoforms (NaAF, NaA(bi)) in cancer patients. A statistically significant increase of Fc fucosylation was observed in tumor stage II and III whereas reverse changes were found for the presence of bisecting GlcNAc. Higher level of fully sialylated glycans and elevated expression of glycans with bisecting GlcNAc were associated with better survival rate. Our findings provide the first evidence that the changes in Fc glycan profile may predict the survival of patients with gastric cancer. Cancer stage-dependent changes in Fc fucosylation and the bisecting N-acteylglucosamine expression as well as an association of several IgG glycoforms with the survival suggest that IgG glycosylation is related to pathogenesis of cancer and progression of the disease.
IntroductionMacrophages play a significant role in the progression of diseases, such as cancer, making them a target for immune‐modulating agents. Trehalose dibehenate (TDB) is known to activate M1‐like macrophages via Mincle, however, the effect of TDB on M2‐like macrophages, which are found in the tumor microenvironment, has not been studied.MethodsqRT‐PCR, flow cytometry, cytokine ELISA, and Western Blotting were used to study the effect of TDB on GM‐CSF and M‐CSF/IL‐4 derived bone marrow macrophages (BMMs) from C57BL/6 and Mincle−/− mice.ResultsTDB treatment up‐regulated M1 markers over M2 markers by GM‐CSF BMMs, whereas M‐CSF/IL‐4 BMMs down‐regulated marker gene expression overall. TDB treatment resulted in Mincle‐independent down‐regulation of CD11b, CD115, and CD206 expression by GM‐CSF macrophages and CD115 in M‐CSF/IL‐4 macrophages. GM‐CSF BMMs produced of significant levels of proinflammatory cytokines (IL‐1β, IL‐6, TNF‐α), which was Mincle‐dependent and further enhanced by LPS priming. M‐CSF BMMs produced little or no cytokines in response to TDB regardless of LPS priming. Western blot analysis confirmed that the absence of cytokine production was associated with a lack of activation of the Syk kinase pathway.ConclusionThis study illustrates that TDB has the potential to differentially regulate M1‐ and M2‐like macrophages in the tumor environment.
Trehalose glycolipids play an important role in the pathogenesis of Mycobacterium tuberculosis and are used as adjuvants for vaccines; however, much still remains unanswered about the mechanisms through which these glycolipids exert their immunomodulatory potential. Recently, the macrophage-inducible C-type lectin Mincle was determined to be the receptor for trehalose glycolipids, yet the role played by Mincle in glycolipid uptake is unknown. Accordingly, we developed several fluorescent trehalose glycolipid reporter systems that can be used to study the uptake of soluble trehalose glycolipids and glycolipid-coated particles by macrophages. Our studies revealed that, although Mincle is essential for the activation of macrophages by trehalose glycolipids, the receptor does not play a role in the uptake of these glycolipids or of glycolipid-coated particles.
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