Association of AXL and PD-L1 expression with clinical outcomes in patients with advanced renal cell carcinoma treated with PD-1 blockade

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 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 metastatic patients receiving PD-1 inhibitor, nivolumab, in the GETUG AFU 26 NIVOREN trial after failure of anti-angiogenic 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, CD20, and the mutational status of the tumor suppressor gene VHL Results: Our results show that high AXL expression levels 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.