SPP1 expression indicates outcome of immunotherapy plus tyrosine kinase inhibition in advanced renal cell carcinoma

ABSTRACT

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.

KEYWORDS:

• Renal cell carcinoma
• SPP1
• immune checkpoint inhibitor
• tyrosine kinase inhibitor
• T cell exhaustion

Acknowledgments

We are sincerely grateful to all authors and data collectors of the JAVELIN Renal 101 trial and the Cancer Genome Atlas database for their data sharing.

Author contributions

Xianglai Xu: Data curation, Formal analysis, Investigation, Writing – original draft. Jinglai Lin: Methodology, Software. Jiahao Wang: Investigation, Writing – original draft. Ying Wang: Investigation. Yanjun Zhu: Supervision, Writing – review & editing. Jiajun Wang: Software, Supervision, Writing – review & editing. Jianming Guo: Conceptualization, Supervision, Writing – review & editing. All authors read and approved the manuscript.

Ethical statement

Approval of the research protocol by an Institutional Reviewer Board: This study was approved by Ethics Review Committees/Institutional Review Boards of Zhongshan Hospital, Fudan University (B2021–119). Informed Consent: All participants involved in this article signed informed consent.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data from the study can be shared with other researchers upon reasonable request, according to the data-sharing policy.

Supplementary materials

Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2024.2350101

Additional information

Funding

This study was funded by grants from the Natural Science Foundation of Fujian Province, China [2023J05297], National Natural Science Foundation of China [81700660, 82200090, 81902898, 82272776], Medical Project of Xiamen [3502Z20214ZD1080], Science Foundation of Zhongshan Hospital (Xiamen), Fudan University [2020ZSXMYS17], Shanghai Sailing Program [19YF1407900], China Urological Oncology Research Fund [H2023-018], and Zhongshan Clinical Research Project [ZSLCYJ202338]. All the sponsors have no roles in the study design, in the collection, analysis, or the interpretation of data.