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.
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.
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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021 Aug 18 [Epub ahead of print]
Stéphane Terry, Cécile Dalban, Nathalie Rioux Leclercq, Julien Adam, Maxime Meylan, Stéphanie Buart, Antoine Bougoüin, Alexandra Lespagnol, Frédéric Dugay, Irelka Colina Moreno, Guillaume Lacroix, James B Lorens, Gro Gausdal, Wolf H Fridman, Fathia Mami-Chouaib, Nathalie Chaput, Benoit Beuselinck, Sylvie Chabaud, Janice Barros Monteiro, Yann Vano, Bernard Escudier, Catherine Sautes-Fridman, Laurence Albiges, Salem Chouaib
INSERM U1186, Institut Gustave Roussy ., Centre Léon Bérard., Rennes University, Rennes University Hospital, Department of Pathology., INSERM U981, Institut Gustave Roussy., Inflammation, complement & cancer, Centre de Recherche des Cordeliers., Institut Gustave Roussy, INSERM U753., Inflammation, Complement and Cancer, Centre de Recherche des Cordeliers., Department of Somatic Cancer Genetics, Pontchaillou Hospital, CHU de Rennes, Rennes, France., CHU Rennes., Centre de Recherche des Cordeliers., Inflammation, Complement and Cancer, Cordeliers Research Center, INSERM UMRS 1138., Department of Biomedicine, University of Bergen, Norway., BerGenBio ASA, BerGenBio ASA., Cordeliers Research Centre, University Paris-Descartes., U1186 INSERM, Institut Gustave Roussy., Laboratory of Immuno-oncology, Institut Gustave Roussy., General Medical Oncology, University Hospitals Leuven., Biostatistic Department, Centre Leon Berard., Translational research, UniCancer Group., Hopital Européen Georges Pompidou., Department of Medical Oncology, Institut Gustave Roussy., Laboratoire Inflammation, complement et cancer, Centre de Recherche des Cordeliers, Inserm UMRS 1138., Department of Cancer Medicine, Institut Gustave Roussy, Université Paris Saclay., Institut Gustave Roussy.