PRDM15 inhibits responses of Tissue-Resident memory T cells by activating PVR/TIGIT axis to mediate gastric cancer immunosuppression.

[INTRODUCTION] Gastric cancer (GC) has shown relatively poor responses to existing immune therapies. The extensive infiltration of tissue-resident memory T cells (T) in tumor microenvironment (TME) is associated with better Overall Survival (OS) in patients treated with immune checkpoint inhibitors (ICIs). However, the precise roles of T cells in cancer immunity and responses to ICIs in GC remain poorly understood.

[OBJECTIVES] We found that the T cells representing the majority of tumor-infiltrating lymphocytes and expressing high level of immune checkpoint TIGIT in GC tissue. This study aims to elucidate the mechanisms through which GC cells modulate T cells by PVR/TIGIT axis to facilitate immune evasion.

[METHODS] The immune status of GC was evaluated by quantifying T cell subsets in GC tissues through flow cytometry. The biological functions and molecular mechanisms by which the oncogenic factor PRDM15 mediates tumor immune evasion were investigated through the PVR/TIGIT axis using transcriptome sequencing, Chromatin immunoprecipitation (ChIP) assay and Co-immunoprecipitation assay. The therapeutic potential of PRDM15/PVR/TIGIT was analyzed using tumor-bearing models.

[RESULTS] We confirmed that PRDM15 promotes the transcription of PVR which is the ligand of TIGIT in GC cells. Aberrantly high expression of PRDM15 in GC tissues was associated with higher TNM stages and T cell immunosuppressive state in GC patients. PRDM15 was found to upregulate the proliferation, invasion and migration of GC cells. When co-cultured with T cells with high TIGIT expression, PRDM15 activated the PVR/TIGIT axis to inhibit T cells activation by upregulating PVR expression in GC cells. Mechanistically, PRDM15 recruited the histone methyltransferase complex PRMT5/Mep50/WDR5 to activate PVR transcription.

[CONCLUSION] This study demonstrated that PRDM15 in GC cells could recruits the histone methyltransferase complex PRMT5/Mep50/WDR5 to promote PVR transcription, thereby activating the PVR/TIGIT axis, which inhibits T cells activation and mediates immune escape and GC progression.