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Purpose:A minority of patients currently respond to single-agent immune-checkpoint blockade (ICB), and strategies to increase response rates are urgently needed. AXL is a receptor tyrosine kinase commonly associated with drug resistance and poor prognosis in many cancer types, including in clear-cell renal cell carcinoma (ccRCC). Recent experimental cues in breast, pancreatic, and lung cancer models have linked AXL with immune suppression and resistance to antitumor immunity. However, its role in intrinsic and acquired resistance to ICB remains largely unexplored.Experimental Design:In this study, tumoral expression of AXL was examined in ccRCC specimens from 316 patients who were metastatic receiving the PD-1 inhibitor nivolumab in the GETUG AFU 26 NIVOREN trial after failure of antiangiogenic therapy. We assessed associations between AXL and patient outcomes following PD-1 blockade, as well as the relationship with various markers, including PD-L1; VEGFA; the immune markers CD3, CD8, CD163, and CD20; and the mutational status of the tumor-suppressor gene von Hippel-Lindau (VHL).Results:Our results show that high AXL-expression level in tumor cells is associated with lower response rates and a trend to shorter progression-free survival following anti–PD-1 treatment. AXL expression was strongly associated with tumor–PD-L1 expression, especially in tumors with VHL inactivation. Moreover, patients with tumors displaying concomitant PD-L1 expression and high AXL expression had the worst overall survival.Conclusions:Our findings propose AXL as candidate factor of resistance to PD-1 blockade, and provide compelling support for screening both AXL and PD-L1 expression in the management of advanced ccRCC.See related commentary by Hahn et al., p. 6619

This file contains 6 supplementary figures and 5 supplementary Tables. Supplementary Figure S1 - Protein expression pattern of AXL in ccRCC specimens. Supplementary Figure S2 - Response rates, Survival and Biomarker analyses according to AXLneg, AXLlow and AXLhigh expression Supplementary Figure S3 - ORR and Progression-Free Survival according to PD-L1 Status alone or by grouping AXL expression plus PD-L1 status Supplementary Figure S4 - High AXL expression plus PD-L1 TC positivity is associated with worse OS in Nivolumab-treated patients in IMDC intermediate-risk/poor-risk group Supplementary Figure S5 - VHL status does not interfere with outcomes or AXL expression upon treatment with Nivolumab Supplementary Figure S6 - Biomarker distribution across AXL groups stratified based on VHL status