Inhibiting HnRNP L-mediated alternative splicing of EIF4G1 counteracts immune checkpoint blockade resistance in Castration-resistant prostate Cancer
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 immun...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558624001507 |
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| author | Xumin Zhou Shilong Cheng Zhongjie Chen Jinming Zhang Jiaqi Wang Qiang Li Xumin Zhou |
| author_facet | Xumin Zhou Shilong Cheng Zhongjie Chen Jinming Zhang Jiaqi Wang Qiang Li Xumin Zhou |
| author_sort | Xumin Zhou |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-0067f327aa124b96964d608832581560 |
| institution | Kabale University |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-0067f327aa124b96964d6088325815602025-02-03T04:16:34ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-02-0160101109Inhibiting HnRNP L-mediated alternative splicing of EIF4G1 counteracts immune checkpoint blockade resistance in Castration-resistant prostate CancerXumin Zhou0Shilong Cheng1Zhongjie Chen2Jinming Zhang3Jiaqi Wang4Qiang Li5Xumin Zhou6General 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 ChinaDepartment of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR ChinaDepartment of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR ChinaDepartment of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR ChinaDepartment of Spinal Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR ChinaGeneral Surgery Center Department of Thyroid Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China; Corresponding authors.General 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; Corresponding authors.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.http://www.sciencedirect.com/science/article/pii/S1476558624001507HnRNP LEIF4G1Alternative splicingImmune checkpoint blockadeResistanceCastration-resistant prostate cancer |
| spellingShingle | Xumin Zhou Shilong Cheng Zhongjie Chen Jinming Zhang Jiaqi Wang Qiang Li Xumin Zhou Inhibiting HnRNP L-mediated alternative splicing of EIF4G1 counteracts immune checkpoint blockade resistance in Castration-resistant prostate Cancer Neoplasia: An International Journal for Oncology Research HnRNP L EIF4G1 Alternative splicing Immune checkpoint blockade Resistance Castration-resistant prostate cancer |
| title | Inhibiting HnRNP L-mediated alternative splicing of EIF4G1 counteracts immune checkpoint blockade resistance in Castration-resistant prostate Cancer |
| title_full | Inhibiting HnRNP L-mediated alternative splicing of EIF4G1 counteracts immune checkpoint blockade resistance in Castration-resistant prostate Cancer |
| title_fullStr | Inhibiting HnRNP L-mediated alternative splicing of EIF4G1 counteracts immune checkpoint blockade resistance in Castration-resistant prostate Cancer |
| title_full_unstemmed | Inhibiting HnRNP L-mediated alternative splicing of EIF4G1 counteracts immune checkpoint blockade resistance in Castration-resistant prostate Cancer |
| title_short | Inhibiting HnRNP L-mediated alternative splicing of EIF4G1 counteracts immune checkpoint blockade resistance in Castration-resistant prostate Cancer |
| title_sort | inhibiting hnrnp l mediated alternative splicing of eif4g1 counteracts immune checkpoint blockade resistance in castration resistant prostate cancer |
| topic | HnRNP L EIF4G1 Alternative splicing Immune checkpoint blockade Resistance Castration-resistant prostate cancer |
| url | http://www.sciencedirect.com/science/article/pii/S1476558624001507 |
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