胸苷激酶1表明肾细胞癌对免疫检查点加酪氨酸激酶抑制的抵抗。

IF 6.6 2区 医学 Q1 Medicine
Cellular Oncology Pub Date : 2025-06-01 Epub Date: 2025-02-26 DOI:10.1007/s13402-025-01048-7
Jiajun Wang, Xianglai Xu, Ying Wang, Yanjun Zhu
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引用次数: 0

摘要

目的:免疫检查点加酪氨酸激酶抑制(IO + TKI)已成为转移性肾细胞癌(RCC)的一线治疗方法,但没有生物标志物可以预测其疗效。胸苷激酶1 (TK1)与肿瘤的免疫逃避密切相关。方法:通过IO + TKI治疗的转移性RCC患者从两个队列(ZS-MRCC, n = 45;标枪-101,n = 726)。高危局部RCC也入组(ZS-HRRCC, n = 40)。在所有队列中,通过rna测序评估TK1,并通过流式细胞术和免疫组织化学评估免疫状况。结果:IO + TKI耐药患者TK1表达升高(p = 0.025)。高tk1组在ZS-MRCC队列(P = 0.008)和Javelin-101队列(P = 0.036)中均显示较差的无进展生存期(PFS)。通过多因素Cox回归,确定高tk1是PFS差的独立因素(HR = 3.855, P = 0.002)。高tk1表达与颗粒酶B+ CD8+ T细胞减少(ρ=-0.22, P = 0.18)、PD1+ CD4+ T细胞增加(ρ= 0.33, P = 0.04)、PDL1+巨噬细胞增加(ρ= 0.45, P)相关。结论:高tk1表达可能是IO + TKI治疗下转移性RCC耐药、PFS差和免疫逃避的潜在指标。新的RF风险评分可能有助于对IO + TKI治疗的患者进行分层。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Thymidine kinase 1 indicates resistance to immune checkpoint plus tyrosine kinase inhibition in renal cell carcinoma.

Purpose: Immune checkpoint plus tyrosine kinase inhibition (IO + TKI) has emerged as the first-line therapy in metastatic renal cell carcinoma (RCC), but no biomarker can predict its efficacy. Thymidine kinase 1 (TK1) is closely associated with immune evasion in tumors.

Methods: Metastatic RCC patients treated by IO + TKI were enrolled from two cohorts (ZS-MRCC, n = 45; Javelin-101, n = 726). High-risk localized RCC were also enrolled (ZS-HRRCC, n = 40). TK1 was assessed by RNA-sequencing in all cohorts, and the immune contexture was assessed by flow cytometry and immunohistochemistry.

Results: Higher TK1 expression was found in patients resistant to IO + TKI therapy (p = 0.025). High-TK1 group showed poor progression-free survival (PFS) in both the ZS-MRCC cohort (P = 0.008) and the Javelin-101 cohort (P = 0.036). By multivariate Cox regression, high-TK1 was determined as an independent factor for poor PFS (hazard ratio (HR) = 3.855, P = 0.002). High-TK1 expression was associated with decreased granzyme B+ CD8+ T cells (ρ=-0.22, P = 0.18), increased PD1+ CD4+ T cells (ρ = 0.33, P = 0.04), increased PDL1+ macrophages (ρ = 0.45, P < 0.001), and increased regulatory T cells (ρ = 0.35, P = 0.03). A novel random forest (RF) risk score was built by machine learning based on TK1 and immunologic parameters. Combined IO + TKI therapy surpassed sunitinib monotherapy in the low RF risk score group (HR = 0.158, P < 0.001), but was inferior to sunitinib in the high RF risk score group (HR, 2.195, P < 0.001).

Conclusion: High-TK1 expression could be a potential indicator for therapeutic resistance, poor PFS and immune evasion in metastatic RCC under IO + TKI therapy. The novel RF risk score may help stratify patients for IO + TKI therapy.

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来源期刊
Cellular Oncology
Cellular Oncology Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
10.40
自引率
1.50%
发文量
0
审稿时长
16 weeks
期刊介绍: The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.
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