Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Urology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China.
Hum Vaccin Immunother. 2024 Dec 31;20(1):2350101. doi: 10.1080/21645515.2024.2350101. Epub 2024 May 13.
Clinical guidelines have recently advised combination therapy involving immunotherapy (IO) and tyrosine kinase inhibitors (TKI) as the first-line therapy approach for advanced renal cell carcinoma (RCC). Nevertheless, there is currently no available biomarker that can effectively distinguish the progression-free survival (PFS). RNA-sequencing and immunohistochemistry were conducted on our cohort of metastatic RCC patients, namely ZS-MRCC, who received combination therapy consisting of IO and TKI. We further applied RNA-sequencing, immunohistochemistry, and flow cytometry to examine the immune cell infiltration and functionality inside the tumor microenvironment of high-risk localized RCC samples. SPP1 expression was significantly higher in non-responders to IO-TKI therapy. Elevated levels of SPP1 were associated with poor PFS in both the ZS-MRCC cohort (HR = 2.73, = .018) and validated in the JAVELIN Renal 101 cohort (HR = 1.61, = .004). By multivariate Cox analysis, SPP1 was identified as a significant independent prognosticator. Furthermore, there existed a negative correlation between elevated levels of SPP1 and the presence of GZMBCD8 T cells (Spearman's ρ= -0.48, < .001). Conversely, SPP1 expression is associated with T cell exhaustion markers. A significant increase in the abundance of Tregs was observed in tumors with high levels of SPP1. Additionally, a machine-learning-based model was constructed to predict the benefit of IO-TKI treatment. High SPP1 is associated with therapeutic resistance and unfavorable PFS in IO-TKI therapy. SPP1 expression have also been observed to be indicative of malfunction and exhaustion in T cells. Increased SPP1 expression has the potential to serve as a potential biomarker for treatment selection of metastatic RCC.
最近的临床指南建议，将免疫疗法（IO）和酪氨酸激酶抑制剂（TKI）联合治疗作为晚期肾细胞癌（RCC）的一线治疗方法。然而，目前尚无有效的生物标志物可以有效区分无进展生存期（PFS）。我们对接受 IO-TKI 联合治疗的转移性 RCC 患者（ZS-MRCC）进行了 RNA 测序和免疫组化分析。我们进一步应用 RNA 测序、免疫组化和流式细胞术检测高危局限性 RCC 样本肿瘤微环境中的免疫细胞浸润和功能。IO-TKI 治疗无应答者的 SPP1 表达明显更高。ZS-MRCC 队列中（HR=2.73，P=.018）和验证队列 JAVELIN Renal 101 中（HR=1.61，P=.004），SPP1 水平升高与较差的 PFS 相关。多变量 Cox 分析表明，SPP1 是一个显著的独立预后因素。此外，SPP1 水平升高与 GZMBCD8 T 细胞的存在呈负相关（Spearman's ρ=-0.48，P<.001）。相反，SPP1 表达与 T 细胞耗竭标志物相关。在 SPP1 水平较高的肿瘤中，Treg 的丰度显著增加。此外，构建了基于机器学习的模型来预测 IO-TKI 治疗的获益。高 SPP1 与 IO-TKI 治疗中的治疗抵抗和不良 PFS 相关。还观察到 SPP1 表达与 T 细胞功能障碍和耗竭相关。SPP1 表达增加可能成为转移性 RCC 治疗选择的潜在生物标志物。
