Abstract
Immunotherapy plus tyrosine kinase inhibitor (IO-TKI) has become the standard first-line therapy for advanced renal cell carcinoma (RCC). However, the modest response rate of IO-TKI therapy and the absence of biomarkers limited the selection of treatment strategies for RCC patients. There were three cohorts enrolled: two from our facility (ZS-MRCC and ZS-HRRCC) and one from a clinical study (JAVELIN-101). By RNA sequencing, the expression of ADAM9 in each sample was measured. By flow cytometry and immunohistochemistry, immune infiltration and T cell function were examined. Primary outcomes were established as treatment response and progression-free survival (PFS). Patients with low-ADAM9 expression had a higher objective response rate (56.5% vs 13.6%, P = 0.01) and longer PFS in both cohorts. In the ZS-HRRCC cohort, the expression of ADAM9 was associated with increased tumor-infiltrating T cells, which was proved by immunohistochemistry (P < 0.05) and flow cytometry (Spearman’s ρ = 0.42, P < 0.001). In the high-ADAM9 group, CD8+ and CD4+ T cells revealed an exhausted phenotype with decreased GZMB (Spearman’s ρ = − 0.31, P = 0.05, and Spearman’s ρ = − 0.49, P < 0.001, respectively), and fewer Macrophages were identified. A predictive RFscore was further constructed by random forest approach, involving ADAM9 and immunologic genes. Only in the subgroup with the lower RFscore did IO-TKI outperform TKI monotherapy. High-ADAM9 expression was associated with immunosuppression and IO-TKI resistance. Expression of ADAM9 was also associated with the exhaustion and dysfunction of T cells. ADAM9-based RFscore has the potential to be used as a biomarker to distinguish the optimal patient treatment methods between IO-TKI and TKI monotherapy.
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Data Availability
The datasets in the current study are open to the public at the TCGA (https://xena.ucsc.edu/) and Javelin Renal 101 clinical trial (https://www.nature.com/articles/s41591-020-1044-8). Further inquiries can be directed to the corresponding authors. The data of our cohorts that support the results of this study are available from the corresponding author upon reasonable request.
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Acknowledgements
We thank those authors who released and shared their datasets on the TCGA databases and Javelin Renal 101 clinical trial.
Funding
This study was funded by grants from the National Natural Science Foundation of China (81700660, 81902898, 81772696, 81974393), Shanghai Sailing Program (19YF1407900), and Experimental Animal Project of Shanghai Science and Technology Commission (19140905200). All these study sponsors have no roles in the study design and in the collection, analysis, and interpretation of data.
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Xianglai Xu and Jiajun Wang conceived and designed the study. Jiajun Wang, Zhaoyi Chen, and Ying Wang contributed to the acquisition, analysis, and interpretation of data. Jiajun Wang and Ying Wang performed the statistical analysis. Jiajun Wang wrote the paper. Yanjun Zhu, Xianglai Xu, and Jianming Guo reviewed the manuscript. Ying Wang and Yanjun Zhu provided technical and material support. Jiajun Wang, Yanjun Zhu, Xianglai Xu, and Jianming Guo contributed to the funding obtaining. Jianming Guo contributed to study supervision. All authors read and approved the manuscript.
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The study followed the Declaration of Helsinki and was approved by the Clinical Research Ethics Committee of Zhongshan Hospital, Fudan University (B2021-119). Informed consent was obtained from each participant.
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251_2022_1292_MOESM1_ESM.jpg
Supplementary file1 Fig. S1 (A-B) The relationship between stage (A) or grade (B) and the expression of ADAM9. P values, Kruskal-Wallis H test. (C) PFS according to ADAM9 expression in the TxNxM1 cases from TCGA cohort. P value, Kaplan-Meier analysis, and log-rank test. (D-E) Association between TILs and ADAM9 expression by immunohistochemistry (D) and flow cytometry (E) in the ZS-HRCC cohort. ρ and P values, Spearman's rank-order correlation (JPG 732 KB)
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Xu, X., Wang, Y., Chen, Z. et al. Unfavorable immunotherapy plus tyrosine kinase inhibition outcome of metastatic renal cell carcinoma after radical nephrectomy with increased ADAM9 expression. Immunogenetics 75, 133–143 (2023). https://doi.org/10.1007/s00251-022-01292-3
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DOI: https://doi.org/10.1007/s00251-022-01292-3