Objective:

This study aimed to investigate the involvement of TBX15 in the immune evasion by gastric cancer (GC) cells, as well as the molecular pathways that regulate TBX15 upstream and downstream.

Methods:

GC and paracancerous tissues were collected to verify the expression of TBX15, MMP14, and METTL3. The co-culture system of GC cell-tumor-associated macrophages (TAMs) and GC cell-CD8+ T cells was constructed to explore the functions of TBX15, MMP14, and METTL3 on the immune evasion by GC cells.

Results:

TBX15, MMP14, and METTL3 were highly expressed in GC tissues. High TBX15 expression predicts a poor prognosis for GC patients. Silencing TBX15 promoted GC cell apoptosis and inhibited tumor development and the activity of proliferation, migration, and invasion. TBX15 targeted the MMP14 promoter. Overexpression of MMP14 attenuated the reduction caused by TBX15 silencing. METTL3 targets TBX15 mRNA and regulates the m6A level of TBX15. TBX15 is associated with macrophage and CD8+ T cell infiltration. In the co-culture system of GC-TAM and GC-CD8+ T cells, TBX15 overexpression alleviated the decrease in M2 polarization and activation of CD8+ T cell antitumor activity caused by METTL3 silencing. However, MMP14 overexpression resulted in TBX15 silence-induced decreases in M1 macrophage polarization and CD8+ T cell activity.

Conclusions:

These data suggested that TBX15, correlated with poor prognosis in GC patients, promotes immune escape in GC cells. TBX15, regulated by m6A methylation, targeted the MMP14 promoter, thereby regulating MMP14 expression. The METTL3/TBX15/MMP14 signaling axis was involved in GC cell development, M2 macrophage polarization and CD8+ T cell anti-tumor activity activation. These findings provide a fundamental experimental rationale for TBX15 as a potential therapeutic target for GC.