Targeting the JMJD6/TGF-? axis in prostate cancer by immunotherapy: A potential treatment based on RNA splicing

Prostate cancer showcases remarkable clinical heterogeneity. Long-term treatment targeting androgen/androgen receptor-axis may drive patients to develop castration-resistant and more aggressive neuroendocrine phenotypes. The tumor immune microenvironment (TIME) presents activation of multiple progression-related programs. It is generally considered that TGF beta secreted by prostate cancer cell leads to inhibitory activity of effector T lym-phocytes and contributes to inhibitory TIME by activation of TGF beta signaling pathway. However, the mechanisms regulating mRNA splicing and expression of TGF beta are poorly understood. Here we hypothesize that Jumonji domain-containing 6 (JMJD6), previously as a histone demethylase, underlies the function of aiding alternative splicing of TGF beta mRNA, which promote TGF beta production and secretion, and activate TGF beta signal pathway from upstream links, eventually forming immunosuppressive TIME and inducing therapeutic resistance. We identify that JMJD6 interacts with multiple splicing cofactors including serine/arginine enriched splicing factor 8 (SRSF8), heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) and heterogeneous nuclear ribonu-cleoprotein K (HNRNPK) based on mass spectrometry analysis. Moreover, the obviously positive relationships occur among JMJD6, SRSF8/HNRNPA2B1/HNRNPK and TGF beta based on database analysis. In view of limited clinical efficacies of using neutralizing antibody of TGF beta, TGF beta receptor inhibitor and TGF-beta/PD-L1 coupled antibodies targeting TGF beta signal pathway and delaying tumor progression, our data provide a novel therapeutic insight on blocking TGF beta production from transcription/mRNA splicing level through targeting JMJD6. Our results suggest that targeting the JMJD6/TGF-beta Axis can combine with immunotherapies targeting TGF beta signal pathway in TIME to achieve great benefits for treating prostate cancer progression. Combination with JMJD6 antagonist and immunotherapy can sensitize the anti-tumor effect produced by targeting TGF beta signal pathway, block the production of TGF beta from the origin and solve the bottleneck of immunotherapy for prostate cancer.

Automated summary

Prostate cancer is clinically heterogeneous and long-term treatment can lead to development of aggressive neuroendocrine phenotypes. The tumor immune microenvironment (TIME) is activated in the progression of prostate cancer. Our study suggests that JMJD6 may aid in alternative splicing of TGF beta mRNA, promoting TGF beta production and secretion and activating the TGF beta signaling pathway. Targeting JMJD6 at the transcription/mRNA splicing level could provide a novel therapeutic approach for blocking TGF beta production and improving immunotherapy efficacy.