Memory/active T cell activation is associated with immunotherapeutic response in fumarate hydratase-deficient renal cell carcinoma
PURPOSE: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and lethal subtype of kidney cancer. However, the optimal treatments and molecular correlates of benefits for FH-deficient RCC are currently lacking.
EXPERIMENTAL DESIGN: A total of 91 patients with FH-deficient RCC from 15 medical centers between 2009 and 2022 were enrolled in this study. Genomic and bulk RNA sequencing (RNA-seq) were performed on 88 and 45 untreated FH-deficient RCCs, respectively. Single-cell RNA-seq was performed to identify biomarkers for treatment response. Main outcomes included disease-free survival (DFS) for localized patients, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for metastatic patients.
RESULTS: In the localized setting, we found that a cell cycle progression signature enabled to predict disease progression. In the metastatic setting, first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI+TKI) combination therapy showed satisfactory safety and was associated with a higher ORR (43.2% vs. 5.6%), apparently superior PFS (median PFS: 17.3 vs. 9.6 months, P=0.016) and OS (median OS: not reached vs. 25.7 months, P=0.005) over TKI monotherapy. Bulk and single-cell RNA-seq data revealed an enrichment of memory and effect T cells in responders to ICI plus TKI combination therapy. Furthermore, we identified a signature of memory and effect T cells that was associated with the effectiveness of ICI plus TKI combination therapy.
CONCLUSIONS: ICI plus TKI combination therapy may represent a promising treatment option for metastatic FH-deficient RCC. A memory/active T cell-derived signature is associated with the efficacy of ICI+TKI but necessitates further validation.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - (2024) vom: 21. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chen, Junru [VerfasserIn] |
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| Anmerkungen: |
Date Revised 21.03.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1158/1078-0432.CCR-23-2760 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM37001698X |
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| 100 | 1 | |a Chen, Junru |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Memory/active T cell activation is associated with immunotherapeutic response in fumarate hydratase-deficient renal cell carcinoma |
| 264 | 1 | |c 2024 | |
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| 500 | |a Date Revised 21.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status Publisher | ||
| 520 | |a PURPOSE: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and lethal subtype of kidney cancer. However, the optimal treatments and molecular correlates of benefits for FH-deficient RCC are currently lacking | ||
| 520 | |a EXPERIMENTAL DESIGN: A total of 91 patients with FH-deficient RCC from 15 medical centers between 2009 and 2022 were enrolled in this study. Genomic and bulk RNA sequencing (RNA-seq) were performed on 88 and 45 untreated FH-deficient RCCs, respectively. Single-cell RNA-seq was performed to identify biomarkers for treatment response. Main outcomes included disease-free survival (DFS) for localized patients, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for metastatic patients | ||
| 520 | |a RESULTS: In the localized setting, we found that a cell cycle progression signature enabled to predict disease progression. In the metastatic setting, first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI+TKI) combination therapy showed satisfactory safety and was associated with a higher ORR (43.2% vs. 5.6%), apparently superior PFS (median PFS: 17.3 vs. 9.6 months, P=0.016) and OS (median OS: not reached vs. 25.7 months, P=0.005) over TKI monotherapy. Bulk and single-cell RNA-seq data revealed an enrichment of memory and effect T cells in responders to ICI plus TKI combination therapy. Furthermore, we identified a signature of memory and effect T cells that was associated with the effectiveness of ICI plus TKI combination therapy | ||
| 520 | |a CONCLUSIONS: ICI plus TKI combination therapy may represent a promising treatment option for metastatic FH-deficient RCC. A memory/active T cell-derived signature is associated with the efficacy of ICI+TKI but necessitates further validation | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Hu, Xu |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Junjie |e verfasserin |4 aut | |
| 700 | 1 | |a Yin, Xiaoxue |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Linmao |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Jingjing |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Jianhui |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yongquan |e verfasserin |4 aut | |
| 700 | 1 | |a Sheng, Xinan |e verfasserin |4 aut | |
| 700 | 1 | |a Dong, Haiying |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xiaodong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xingming |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Jiayu |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Haolin |e verfasserin |4 aut | |
| 700 | 1 | |a Yao, Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jiyan |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Yali |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Zhibin |e verfasserin |4 aut | |
| 700 | 1 | |a He, Zhengyu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yaodong |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Ni |e verfasserin |4 aut | |
| 700 | 1 | |a Nie, Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Mengni |e verfasserin |4 aut | |
| 700 | 1 | |a Pan, Xiuyi |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yuntian |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Haoyang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yaowen |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Yanfeng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Sha |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Jinge |e verfasserin |4 aut | |
| 700 | 1 | |a Dai, Jindong |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Zilin |e verfasserin |4 aut | |
| 700 | 1 | |a Zeng, Yuhao |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Zhipeng |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Haojie |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Zhenhua |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Pengfei |e verfasserin |4 aut | |
| 700 | 1 | |a Zeng, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Guangxi |e verfasserin |4 aut | |
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