SPP1 expression indicates outcome of immunotherapy plus tyrosine kinase inhibition in advanced renal cell carcinoma
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 pro...
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| Format: | Article |
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Taylor & Francis Group
2024-12-01
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| Series: | Human Vaccines & Immunotherapeutics |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/21645515.2024.2350101 |
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| author | Xianglai Xu Jinglai Lin Jiahao Wang Ying Wang Yanjun Zhu Jiajun Wang Jianming Guo |
| author_facet | Xianglai Xu Jinglai Lin Jiahao Wang Ying Wang Yanjun Zhu Jiajun Wang Jianming Guo |
| author_sort | Xianglai Xu |
| collection | DOAJ |
| description | 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, p = .018) and validated in the JAVELIN Renal 101 cohort (HR = 1.61, p = .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 GZMB+CD8+ T cells (Spearman’s ρ= −0.48, p < .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. |
| format | Article |
| id | doaj-art-d649589a5d90421d84ffd55e1e509cc5 |
| institution | OA Journals |
| issn | 2164-5515 2164-554X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Human Vaccines & Immunotherapeutics |
| spelling | doaj-art-d649589a5d90421d84ffd55e1e509cc52025-08-20T02:16:40ZengTaylor & Francis GroupHuman Vaccines & Immunotherapeutics2164-55152164-554X2024-12-0120110.1080/21645515.2024.2350101SPP1 expression indicates outcome of immunotherapy plus tyrosine kinase inhibition in advanced renal cell carcinomaXianglai Xu0Jinglai Lin1Jiahao Wang2Ying Wang3Yanjun Zhu4Jiajun Wang5Jianming Guo6Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, ChinaDepartment of Urology, Zhongshan Hospital, Fudan University, Shanghai, ChinaDepartment of Urology, Zhongshan Hospital, Fudan University, Shanghai, ChinaDepartment of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, ChinaDepartment of Urology, Zhongshan Hospital, Fudan University, Shanghai, ChinaDepartment of Urology, Zhongshan Hospital, Fudan University, Shanghai, ChinaDepartment of Urology, Zhongshan Hospital, Fudan University, Shanghai, ChinaClinical 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, p = .018) and validated in the JAVELIN Renal 101 cohort (HR = 1.61, p = .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 GZMB+CD8+ T cells (Spearman’s ρ= −0.48, p < .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.https://www.tandfonline.com/doi/10.1080/21645515.2024.2350101Renal cell carcinomaSPP1immune checkpoint inhibitortyrosine kinase inhibitorT cell exhaustion |
| spellingShingle | Xianglai Xu Jinglai Lin Jiahao Wang Ying Wang Yanjun Zhu Jiajun Wang Jianming Guo SPP1 expression indicates outcome of immunotherapy plus tyrosine kinase inhibition in advanced renal cell carcinoma Human Vaccines & Immunotherapeutics Renal cell carcinoma SPP1 immune checkpoint inhibitor tyrosine kinase inhibitor T cell exhaustion |
| title | SPP1 expression indicates outcome of immunotherapy plus tyrosine kinase inhibition in advanced renal cell carcinoma |
| title_full | SPP1 expression indicates outcome of immunotherapy plus tyrosine kinase inhibition in advanced renal cell carcinoma |
| title_fullStr | SPP1 expression indicates outcome of immunotherapy plus tyrosine kinase inhibition in advanced renal cell carcinoma |
| title_full_unstemmed | SPP1 expression indicates outcome of immunotherapy plus tyrosine kinase inhibition in advanced renal cell carcinoma |
| title_short | SPP1 expression indicates outcome of immunotherapy plus tyrosine kinase inhibition in advanced renal cell carcinoma |
| title_sort | spp1 expression indicates outcome of immunotherapy plus tyrosine kinase inhibition in advanced renal cell carcinoma |
| topic | Renal cell carcinoma SPP1 immune checkpoint inhibitor tyrosine kinase inhibitor T cell exhaustion |
| url | https://www.tandfonline.com/doi/10.1080/21645515.2024.2350101 |
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