The following is a summary of “Bladder-cancer-derived exosomal circRNA_0013936 promotes suppressive immunity by up-regulating fatty acid transporter protein 2 and down-regulating receptor-interacting protein kinase 3 in PMN-MDSCs,” published in the March 2024 issue of Oncology by Shi et al.
In the context of tumor immune tolerance and the inherent challenges in cancer immunotherapy, the role of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) emerges as a significant contributor. This study delves into the intricate mechanisms underlying the immunosuppressive activity of PMN-MDSCs within the milieu of bladder cancer (BCa), spotlighting the pivotal involvement of bladder cancer-derived exosomal circRNA_0013936.
The findings elucidate that circRNA_0013936, enriched within BCa-derived exosomes, exerts a regulatory influence on PMN-MDSCs by modulating the expression profiles of fatty acid transporter protein 2 (FATP2) and receptor-interacting protein kinase 3 (RIPK3). Employing an array of experimental techniques, including RNA sequencing, Western blotting, immunohistochemistry, immunofluorescence, qRT-PCR, ELISA, and flow cytometry, the researchers decipher the intricate interplay orchestrated by circRNA_0013936 in driving the immunosuppressive phenotype of PMN-MDSCs. Mechanistically, the study delineates a cascade wherein circRNA_0013936 acts as a molecular sponge, sequestering miR-320a and miR-301b, thereby relieving their inhibitory effects on JAK2 and CREB1, respectively. Consequently, this regulatory axis culminates in the upregulation of FATP2 via the circRNA_0013936/miR-320a/JAK2 pathway and the downregulation of RIPK3 via the circRNA_0013936/miR-301b-3p/CREB1 pathway within PMN-MDSCs. Notably, these alterations in the expression profiles of key mediators significantly impede the effector functions of CD8+ T cells, underscoring the potent immunomodulatory capabilities of circRNA_0013936 within the tumor microenvironment.
The findings shed light on the intricate molecular mechanisms underpinning immune evasion in bladder cancer and unveil promising avenues for developing targeted therapeutic interventions to mitigate the immunosuppressive milieu orchestrated by PMN-MDSCs. Thus, unraveling the regulatory networks governed by BCa-derived exosomal circRNA_0013936 holds immense potential in guiding future clinical strategies tailored towards ameliorating the therapeutic outcomes in bladder cancer patients.
Source: molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-01968-2
