Inhibiting HnRNP L-mediated alternative splicing of EIF4G1 counteracts immune checkpoint blockade resistance in
Xumin Zhou1, Shilong Cheng2, Zhongjie Chen2
1General Surgery Center Department of Thyroid Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China; Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China.
Abstract:
Immunotherapy with checkpoint inhibitors produced significant clinical responses in a subset of cancer patients who were resistant to prior therapies. However, Castration-resistant prostate cancer (CRPC) is seriously lack of T cell infiltration, which greatly limits the clinical application of immunotherapy, but the mechanism is unclear. In the present study, in silico analyses and experimental data show that HnRNP L was significantly negatively correlated with CD4+ and CD8+ T cells infiltration in patients; besides, we found deficiency of HnRNP L recruites CD4+ and CD8+ T cells infiltration and impairs tumorigenesis. Mechanically, HnRNP L enhanced the translation of c-Myc and then promoted CXCL8 secretion via alternative splicing of EIF4G1. In vivo, inhibition of EIF4G1 by the inhibitor, SBI-0640756, attenuated HnRNP l-induced tumor progression and immunosuppressive activity. And most of all, therapeutic synergy between HnRNP L knockdown and Anti-PD-1 could significantly suppress xenograft prostate cancer growth. In summary, this study revealled the molecular mechanism of HnRNP L regulating the immune infiltration, which provides a new theoretical basis for overcoming the limitation of immunotherapy for CRPC.
Insights
Researchers found that reducing HnRNP L protein levels boosts T cell infiltration in Castration-resistant prostate cancer (CRPC). This approach, combined with Anti-PD-1 therapy, significantly suppressed tumor growth, offering a new strategy for CRPC immunotherapy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immunotherapy with checkpoint inhibitors shows promise in cancer treatment but faces limitations in specific cancers like Castration-resistant prostate cancer (CRPC).
- CRPC exhibits poor T cell infiltration, hindering the effectiveness of current immunotherapies, with the underlying mechanisms remaining unclear.
Purpose of the Study:
- To elucidate the mechanism by which HnRNP L influences immune cell infiltration in CRPC.
- To explore the therapeutic potential of targeting HnRNP L and its downstream pathways for enhancing immunotherapy in CRPC.
Main Methods:
- In silico analyses and experimental validation to assess the correlation between HnRNP L and T cell infiltration.
- Investigation of HnRNP L's role in c-Myc translation and CXCL8 secretion via EIF4G1 alternative splicing.
- In vivo studies using EIF4G1 inhibitor (SBI-0640756) and combination therapy (HnRNP L knockdown with Anti-PD-1) in xenograft models.
Main Results:
- HnRNP L was found to be negatively correlated with CD4+ and CD8+ T cell infiltration in CRPC patients.
- HnRNP L deficiency promoted T cell infiltration and impaired tumor growth.
- HnRNP L enhances c-Myc translation and promotes CXCL8 secretion through EIF4G1 alternative splicing.
- Inhibition of EIF4G1 or HnRNP L knockdown, particularly in combination with Anti-PD-1, significantly suppressed tumor progression and immunosuppressive activity.
Conclusions:
- This study reveals HnRNP L as a key regulator of immune infiltration in CRPC by modulating c-Myc translation and CXCL8 secretion.
- Targeting HnRNP L offers a novel strategy to overcome immune evasion in CRPC.
- The combination of HnRNP L knockdown and Anti-PD-1 immunotherapy demonstrates significant therapeutic synergy, providing a new basis for treating CRPC.
