TFF3 and PVRL2 co-targeting identified by multi-omics approach as an effective cancer immunosuppression strategy

The immunosuppressive tumour microenvironment (TME) plays a critical role in cancer progression and relapse by significantly influencing cancer pathogenesis through autocrine and paracrine signalling. Trefoil factor 3 (TFF3), a secreted protein, has been implicated in modulating the TME to promote cancer advancement. Herein, we investigated the potential association between TFF3 and key immunosuppressive TME components to distinguish a co-targetable oncotherapeutic strategy.

The TFF3-PVRL2 association were identified and investigated by integrating multiple bioinformatic-tools. The virtual compound screening for PVRL2 inhibitors was done with EasyVS. The TFF3-PVRL2 protein-level correlation was validated by immunoblotting, and the effectiveness of co-inhibiting TFF3 and PVRL2 was assessed using siRNA and AMPC (a TFF3 inhibitor).

Analysis of the TISIDB database revealed a positive correlation between TFF3 and PVRL2 mRNA levels across multiple cancer types. This correlation was confirmed at the protein level through immunoblot analysis. Further evaluation using TCGA pan-cancer datasets demonstrated that TFF3 and PVRL2 interact to establish an immunosuppressive TME, promoting cancer progression in BRCA, LUAD, PAAD, PRAD, and STAD. Enrichment analyses of positively correlated genes, PPI network hub proteins, and ceRNA networks involving TFF3 and PVRL2, conducted using LinkedOmics, STRING, and Cytoscape, provided insights into their potential co-functions in cancer. A cell-based assay was performed to evaluate the combined therapeutic efficacy of targeting both, TFF3 and PVRL2 and virtual screening identified potential drugs for inhibiting PVRL2.

PVRL2 has emerged as a promising immunoinhibitory target with significant associations with TFF3 and represents a key co-targetable molecule for effective oncotherapeutic strategies.