MEST promotes immune escape in gastric cancer by downregulating MHCI expression via SHP2

Background: Immune escape is a major obstacle to T-cell-based immunotherapy for cancers such as gastric Cancer (GC). Mesoderm-specific transcript (MEST) is a tumor-promoting factor that regulates multiple oncogenic signaling pathways. However, the role of MEST-mediated immune escape is unclear.

Methods: Bioinformatics analysis of MEST expression and enrichment pathways were performed Quantitative Reverse transcription PCR (qPCR) or western blot was used to detect the expression of MEST, Src homology region 2-containing protein tyrosine Phosphatase 2 (SHP2), Major histocompatibility class I (MHCI)-related genes. Cell function was assessed by Cell Counting Kit (CCK)-8, Transwell, Lactate Dehydrogenase (LDH) kit, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry (IHC). Xenograft nude mice and immune-reconstructed mice were used to test the effects of different treatments on tumor growth and immune escape in vivo.

Results: MEST was upregulated in GC and promoted tumor proliferation, migration, and invasion. Rescue experiments revealed that TNO155 treatment or knockdown of SHP2 promoted the killing ability of CD8⁺ T cells and the expression of granzyme B (GZMB) and interferon-gamma (IFN-γ), and MEST overexpression reversed the effect. In vivo experiments confirmed that MEST promoted tumor growth, knockdown of MEST inhibited immune escape in GC, and that combination treatment with anti-PD-1 improved anti-tumor activity.

Conclusion: In this study, we demonstrated that MEST inhibited IFN-γ secretion from CD8+ T cells by up-regulating SHP2, thereby downregulating MHCI expression in GC cells to promote immune escape and providing a new T cell-based therapeutic potential for GC.

Gastric cancer; IFN-γ; Immune escape; MEST; MHCI; SHP2.