AXL expression reflects tumor-immune cell dynamics impacting outcome in non-small cell lung cancer patients treated with immune checkpoint inhibitor monotherapy.

Autor:	Rayford A; Department of Biomedicine and Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway., Gärtner F; Department of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway.; Department of Clinical Science, Faculty of Medicine, University of Bergen, Bergen, Norway., Ramnefjell MP; Department of Pathology, Haukeland University Hospital, Bergen, Norway.; Department of Clinical Medicine and Centre for Cancer Biomarkers, Faculty of Medicine, University of Bergen, Bergen, Norway., Lorens JB; Department of Biomedicine and Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway., Micklem DR; BerGenBio ASA, Bergen, Norway., Aanerud M; Department of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway.; Department of Clinical Science, Faculty of Medicine, University of Bergen, Bergen, Norway., Engelsen AST; Department of Biomedicine and Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway.; Department of Clinical Medicine and Centre for Cancer Biomarkers, Faculty of Medicine, University of Bergen, Bergen, Norway.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Aug 21; Vol. 15, pp. 1444007. Date of Electronic Publication: 2024 Aug 21 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1444007
Abstrakt:	Introduction: AXL receptor expression is proposed to confer immune-checkpoint inhibitor (ICI)-resistance in non-small cell lung cancer (NSCLC) patients. We sought to interrogate AXL expression in conjunction with mutational and tumor-microenvironmental features to uncover predictive mechanisms of resistance in ICI-treated NSCLC patients. Methods: Tumor samples from 111 NSCLC patients treated with ICI-monotherapy were analyzed by immunohistochemistry for tumor- and immune-AXL expression. Subsets of patients were analyzed by whole-exome sequencing (n = 44) and imaging mass cytometry (n = 14). Results were related to ICI-outcome measurements. Results: Tumor-cell AXL expression correlated with aggressive phenotypic features including reduced OS in patients treated with ICIs ( P = 0.04) after chemotherapy progression, but conversely associated with improved disease control ( P = 0.045) in ICI-treated, PD-L1 high first-line patients. AXL+ immune-cell infiltration correlated with total immune-cell infiltration and improved overall outcomes (PFS: P = 0.044, OS: P = 0.054). Tumor-cell AXL-upregulation showed enrichment in mutations associated with PD-L1-upregulation and ICI-response such as MUC4 and ZNF469 , as well as adverse mutations including CSMD1 and LRP1B which associated with an immune-suppressed tumor phenotype and poor ICI prognosis particularly within chemotherapy-treated patients. Tumor mutational burden had no effect on ICI-outcomes and was associated with a lack of tumor-infiltrating immune cells. Spatial-immunophenotyping provided evidence that tumor-cell AXL-upregulation and adverse mutations modulate the tumor microenvironment in favor of infiltrating, activated neutrophils over anti-tumor immune-subsets including CD4 and CD8 T-cells. Conclusion: Tumor-cell AXL-upregulation correlated with distinct oncotypes and microenvironmental immune-profiles that define chemotherapy-induced mechanisms of ICI-resistance, which suggests the combination of AXL inhibitors with current chemoimmunotherapy regimens can benefit NSCLC patients. Competing Interests: JL and DM are founders of BerGenBio ASA. JL and AR were previously employed by BerGenBio ASA, and DM is currently employed by BerGenBio ASA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Rayford, Gärtner, Ramnefjell, Lorens, Micklem, Aanerud and Engelsen.)
Databáze:	MEDLINE
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