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Effects of PYCR1 on prognosis and immunotherapy plus tyrosine kinase inhibition responsiveness in metastatic renal cell carcinoma patients.
Xu, Xianglai; Wang, Ying; Hu, Xinyu; Zhu, Yanjun; Wang, Jiajun; Guo, Jianming.
Afiliación
  • Xu X; Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • Wang Y; Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • Hu X; Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Wenzhou Medical University, Wenzhou, Zhejiang 325015, China.
  • Zhu Y; Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: zhu.yanjun@zs-hospital.sh.cn.
  • Wang J; Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: w.jiajun@hotmail.com.
  • Guo J; Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: guo.jianming@zs-hospital.sh.cn.
Neoplasia ; 43: 100919, 2023 09.
Article en En | MEDLINE | ID: mdl-37517099
BACKGROUND: Immunotherapy plus tyrosine kinase inhibitor (IO-TKI) has become the first-line management for metastatic renal cell carcinoma (RCC), despite the absence of biomarkers. Recently, pyrroline-5-carboxylate reductase 1 (PYCR1) and proline metabolism have been reported regulatory roles in the anti-tumor response. METHODS: There were three cohorts enrolled: two from our institution (ZS-MRCC and ZS-HRRCC) and one from a clinical trial (JAVELIN-101). The PYCR1expression in each sample was evaluated by RNA sequencing. Flow cytometry and immunohistochemistry were performed to assess immune infiltration. Single-cell RNA-seq (scRNA-seq) data was used for cluster analysis of T cells and macrophages. Primary endpoints were set as response and progression-free survival (PFS). RESULTS: Patients in the low-PYCR1 group had greater objective response rate (52.2% vs 18.2%) and longer PFS in both cohorts (ZS-MRCC cohort, P=0.01, HR=2.80; JAVELIN-101 cohort, P<0.001, HR=1.85). In responders, PYCR1 expression was decreased (P<0.05). In the high PYCR1 group, CD8+ T cells exhibited an exhausted phenotype with decreased GZMB (Spearman's ρ=-0.36, P=0.02). scRNA-seq revealed tissue-resident memory T (Trm) (P<0.05) and tissue-resident macrophage (P<0.01) were decreased in samples with high PYCR1 expression. A machine learning score was further built by random forest, involving PYCR1 and Trm markers. Only in the subgroup with the lower RFscore did IO+TKI show a favorable outcome, compared to TKI monotherapy. CONCLUSIONS: Immunosuppression and IO+TKI resistance were correlated with high PYCR1 expression. T cell exhaustion and dysfunction were also related with the expression of PYCR1. PYCR1 has the potential to be employed as a biomarker to discriminate between IO+TKI and TKI monotherapy as the optimal patient treatment strategy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Células Renales / Neoplasias Renales Tipo de estudio: Clinical_trials / Prognostic_studies Límite: Humans Idioma: En Revista: Neoplasia Asunto de la revista: NEOPLASIAS Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Células Renales / Neoplasias Renales Tipo de estudio: Clinical_trials / Prognostic_studies Límite: Humans Idioma: En Revista: Neoplasia Asunto de la revista: NEOPLASIAS Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos