Unfavorable immunotherapy plus tyrosine kinase inhibition outcome of metastatic renal cell carcinoma after radical nephrectomy with increased ADAM9 expression

AbstractImmunotherapy 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’sρ = 0.42,P <  0.001). In the high-ADAM9 group, CD8+ and CD4+ T cells revealed an exhausted phenotype with decreased GZMB (Spearman ’sρ =  − 0.31,P = 0.05, and Spearman’sρ =  − 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 monoth...
Source: Immunogenetics - Category: Genetics & Stem Cells Source Type: research