One of the most prevalent malignant tumors of the digestive tract is gastric cancer (GC), which ranks fifth in incidence and fourth in death globally (Sung et al., 2021). Despite the declining incidence of GC due to advancements in early diagnostic techniques, the mortality rate remains high for patients in advanced stages who are not eligible for surgical treatment, and effective treatment options are still lacking (Smyth et al., 2020). The cornerstone of GC treatment is surgery, which is presently the only procedure that can remove GC (Smyth et al., 2020, Johnston and Beckman, 2019). However, the majority of patients are already in the late stages at diagnosis because of the occult nature of GC and the lack of particular symptoms (Sato et al., 2020). Therefore, it is crucial to find new, accurate biomarkers and create cutting-edge treatment plans for GC.
The investigation of tumor immune microenvironment has gained popularity recently, particularly the connection of tumor immune escape with the immune environment. Immune therapies, represented by programmed cell death 1 (PD-1)/ programmed death-ligand 1 (PD-L1) inhibitors, have made breakthrough advancements in this field (Smyth et al., 2016). For instance, Wang et al (Wang et al., 2021a). demonstrated that PDI-1, a small molecule antagonist of PD-1/PD-L1 interaction, exhibits effective anti-tumor activity both in vitro and in vivo, mitigating PD-1/PD-L1-induced T cell exhaustion. It can be used in place of or in addition to monoclonal antibodies as an immune checkpoint inhibitor. However, tumor immune escape can impact the efficacy of immune therapy in GC, leading to investigations into the mechanisms of tumor immune escape. Shi et al (Shi et al., 2022). manifested that Dickkopf-1 drives tumor immune escape and hinders anti-PD-1 therapy through macrophage immunosuppression. Li et al (Li et al., 2022). discovered that Circ_0008287 competitively binds microRNA-548c-3p, increasing chloride channel protein 1 (CLIC1) expression, which inhibits CD8+ T cell function and promotes immune escape in GC. MEST is associated with immune infiltration in ovarian cancer (Zhang et al., 2022), but the role of MEST expression in GC cells in immune regulation remains unclear. Therefore, this study aimed to further dissect the role of MEST in the immune escape of GC cells and provide new insights into inhibiting immune escape in GC.
On chromosome 7q32, there is a paternally imprinted gene called mesoderm-specific transcript (MEST). It is also known as paternally expressed gene 1 (PEG1) and has preferential expression from the paternal allele in embryonic tissues (Wang et al., 2021b). Chen et al., (2019). disclosed that MEST is upregulated in breast cancer tissues and its methylation level is negatively regulated by zinc finger protein 57 (ZFP57) protein. High methylation of MEST inhibits tumor development by suppressing the Wnt/β-catenin pathway. Wang et al. (2021b). discovered that in lung cancer, by coordinating the IkappaBalpha/NF-kappaB (IκBα/NF-κB) pathway and interacting with valosin containing protein (VCP), MEST aids in invasion and metastasis. Li et al. (2023a). manifested that miR-29c-3p hinders the development of GC by suppressing MEST. However, there have been no reports on the role of MEST in immune modulation in GC. Therefore, it is important to elucidate molecular mechanisms by which MEST influences immune escape in GC and improve the effectiveness of immune therapy.
Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) is a cytoplasmic protein tyrosine phosphatase (PTP) that regulates receptor tyrosine kinase (RTK) signaling. Aberrant SHP2 activity has been implicated in all stages of tumor initiation, progression, and metastasis (Wang et al., 2022, Chai et al., 2024). However, the precise role of SHP2 in GC metastasis remains incompletely understood. In this study, we demonstrated the upregulation of MEST in GC and its promotion of in vitro proliferation, migration, and invasion of cancer cells, as well as in vivo tumor growth. Furthermore, we found that co-culturing MEST knockdown or overexpressing cells with CD8+ T cells resulted in the downregulation of MHCI expression by overexpressing MEST and promoted the proliferation, migration, and invasion of GC cells. Mechanistically, MEST upregulates SHP2 to mediate the expression of MHCI, thereby inhibiting the cytotoxicity of CD8+ T cells. Our work provides a novel immune evasion mechanism for GC patients undergoing immunotherapy and identifies a promising new target for therapeutic intervention.