Although MAGEH1 is rarely examined, it is known to be upregulated in activated Treg and CD8 + T cells. Recent investigates have stressed the importance of MAGEH1 in tumorigenesis and cancer development [17–19, 21, 25]. In this study, variations in MAGEH1 expression levels appeared to associate with prognosis in different cancer types. MAGEH1 highly expressed correlated with a favorable prognosis in LUAD and PRAD and worsened the prognosis in STAD and BRCA. Unexpectedly, the increased expression of MAGEH1 was beneficial to the outcome of GC patients with adjuvant therapy, pointing out the MAGEH1’s prediction for tumor efficacy. Furthermore, we found that STAD and LGG have different patterns for relevance between immune infiltration and MAGEH1. Therefore, this work provides insights into MAGEH1 as a biomarker for prognosis and therapeutic effect of GC from the tumor immunology viewpoint, which contributes to future mechanism research and the development of immunotherapy.
Here we profiled the difference of MAGEH1 expression and the visualization of prognostic landscape in various tumors utilizing data from Oncomine, PrognoScan and TCGA. Compare to normal tissues, the mRNA levels of MAGEH1 varied among different tumors, and most of them were down-regulated. For example, decreased expression of MAGREH1 in liver cancer tissues corroborates the previous finding  (Fig. 1a and Table S1.). This might be due to certain factors leading to gene silencing, such as transformation-dependent DNA hypermethylation, which is common in cancer cells . However, further investigates are needed to determine the specific relationship between MAGEH1 and methylation. In multiple databases, high MAGEH1 expression dramatically linked to better survival of LUAD and PAAD, and worse prognosis of STAD and BRCA, even though there are remarkable variations among different databases due to diversities in sample collection methods, processing standards, as well as samples themselves (Fig. 2, Table S1, Figure S1,3). Unlike De Simone , who argued highly expressed MAGEH1 predicted a poor 5-year survival of NSCLC patients after adjusting for T cell density, we found LUAD patients with elevated MAGEH1 was remarked related to positive prognosis (Fig. 2 and Figure S1). The different range of tumor types included may account for this contradiction, such as MAGEH1 had a correlation with LUAD prognosis in lung cancer, rather than LUSC (Figure S1). Moreover, various clinical trial endpoints (Figure S1), as well as treatment methods in the study population may lead to diversity in results. Therefore, further research is required, including more patients and more detailed and improved designs. In addition, MAGEH1 was an adverse prognostic factor for GC in stage N1, M0, intestinal and diffuse by Lauren classification, as well as surgery only (Fig. 3). Taken together, MAGEH1 may be a promising prognostic marker for gastric, lung, breast, and prostate cancers.
Interestingly, in the treatment of GC, the elevated expression of MAGEH1 in patients with adjuvant 5-FU was substantially correlated with a favorable prognosis, which differed from whose surgery alone. We speculate MAGEH1 can reverse 5-FU resistance of GC. Over-expression of MAGEH1 has been reported to overcome melanoma resistance to current therapies by interacting with the juxtamembrane region of p75 neurotrophic receptor . Disordered apoptosis is linked to cancer treatment resistance . While 5-FU interferes with DNA replication by inhibiting thymidylate synthase, and consequently, apoptosis and cell cycle arrest , and its effect is limited by the drug resistance of GC. Therefore, it is reasonable to consider that the anti-apoptotic effect of MAGEH1 can partly overcome the tumor resistance to 5-FU and thus improve the prognosis of patients. Up to now, there is little published data on the relationship between MAGEH1 and GC. Additional research is needed to validate this hypothesis, which may help to better define patients who are clinically appropriate to receive adjuvant chemotherapy. This result points to MAGEH1 as a predictive factor responding to post-surgical chemotherapy, rather than being only a prognostic indicator.
Another finding was the association of MAGEH1 expression with varying degrees of immune infiltrates in TME, especially in STAD. TME contains tumor cells and other cells, with tumor-infiltrating lymphocytes accounts for a large proportion. Accumulation of TAMs and Tregs in the TME is a major element in immune evasion and immunosuppression, thus promoting tumor growth and invasion. Moreover, a variety of immunoinfiltrating cells contained in the TME, also participate in cancer development . MAGEH1 expression was negatively correlated to tumor purity in STAD, contrary to the correlation in LGG, which denotes it is relatively enriched in tumor cells in STAD. Therefore, the assessment regarding the MAGEH1-immune infiltration relationship adjusted the purity of the tumor to obviate the confounding effects by tumor purity . We found that MAGEH1 expression optimistically associated with the 6 immune infiltrating cells in STAD, while most negatively correlated in LGG, as expected. This also reflects the heterogeneity of tumors and various roles of MAGEH1 in different tumors.
Meanwhile, the MAGEH1 and immune-related markers relevance also demonstrate MAGEH1 in the regulation of tumor immunity in STAD. Our results revealed a strong link between MAGEH1 and neutrophils. We know that neutrophils regulate many malignance-related behaviors of cancer cells, such as migration and invasion, and may accelerate GC progression by inhibiting T cell function . Under certain assumptions, we can be construed that MAGEH1 may partially inhibit T cell function in the regulation of neutrophils, but not in the way of PD-1 dependence. Interestingly, MAGEH1 was positively correlated with immune markers regarding TAM, monocytes, macrophages, and Treg cells. Although we cannot account for this phenomenon by describing a cell-specific mechanism, clues may be found from ex-pressed markers concerning TAM. The most critical pathways for TAM recruitment and proliferation are the CSF-1 /CSR-1 signal and the CCL2/CCR2 axis , which are crucial for macrophage survival and M1 to M2 transformation. What’s more, some drugs inhibiting TAM recruitment have achieved definite clinical efficacy . The strong correlation between CSF-1, CCL2, M2, and TAM-related immune markers and MAGEH1 reveals the potential regulatory effect of MAGEH1 on the recruitment of monocytes/macrophages, Tregs and M2 polarization. Tumor-infiltrating Tregs can inhibit anti-cancer immunity, thus hindering immunosurveillance and hampering effective antitumor immune responses, sequentially accelerating tumor progression in a broad range of cancer types including GC . FOXP3 and TGF-β are essential for Tregs to regulate effector T cells’ function [35, 36]. Based on the strong correlation between FOXP3, TGF-β and MAGEH1, presumably, MAGEH1 is a potential marker for the tumor immunization of Tregs, influencing the immune response of effector T cells, thereby promoting tumor development. Although the results showed that there was positive relevance between MAGEH1 and CD8 + T cell (Fig. 4, Table 1, 2), MAGEH1 may play a negative role in interfering with CD8 + T cell functions by forming a complex dynamic coordination network with various tumor-infiltrating immune cells (Tregs, TAMs, neutrophils) within TME thus facilitating tumor immune escape. The analysis of the relationship between MAGEH1 and tumor immunogenicity represents a new aspect of MAGEH1 research and highlights the importance of studying the immunotherapeutic effect of MAGEH1 in different tumor types in the future.
Recent work about MAGEH1 may provide some explanations for the potential mechanisms. MAGEH1 may act as E3 ubiquitin ligase, which affects the function or survival of Treg in cancer tissues and accelerates tumor growth and metastasis [37, 38]. Increased expression of MAGEH1 has been reported in numerous tumors' Treg cells, such as breast cancer, CRC, and malignant cell lung cancer [21, 37]. Indeed, Tregs have been emphasized in accelerating tumorigenesis and progression by specifically inhibiting tumor-reactive T cells . Besides, altered subcellular localization of MAGEH1 may affect its function. MAGEH1 is mainly localized to the nucleus in normal cells but is predominantly detected in the cytoplasm of tumor cells . The subcellular localization of proteins is vital for their physiological function . MAGEH1 may transfer from nucleus to cytoplasm, afterwards the different domains and subcellular location of MAGEH1 affect its subcellular functions, such as regulating cell cycle and promoting apoptosis [15, 16, 25, 29].
However, despite the integration of information from multiple databases to analyze the expression and the impact of MAGEH1 on the oncologic outcome, the mechanisms of MAGEH1 have not been fully elucidated in cell and animal studies. Moreover, potential epigenetic mechanisms of MAGEH1 are yet to be explored concerning prognosis. Besides, due to some conflicting findings from different databases, we still can't make a blanket statement about MAGEH1.