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

• DOI: 10.3389/fimmu.2024.1444007
• Publication Date: 2024-08-22T07:53:02Z
• Authors: Austin Rayford; Fabian Gärtner; Maria P. Ramnefjell; James B. Lorens; David R. Micklem; Marianne Aanerud; Agnete S. T. Enge...
• Keywords: Immune checkpoint; Tumor progression

Introduction AXL receptor expression is proposed to confer immune-checkpoint inhibitor (ICI)-resistance in non-small cell lung cancer (NSCLC) patients. We sought interrogate conjunction with mutational and tumor-microenvironmental features uncover predictive mechanisms of resistance ICI-treated NSCLC Methods Tumor samples from 111 patients treated ICI-monotherapy were analyzed by immunohistochemistry for tumor- immune-AXL expression. Subsets whole-exome sequencing (n = 44) imaging mass cytometry 14). Results related ICI-outcome measurements. Tumor-cell correlated aggressive phenotypic including reduced OS ICIs ( P 0.04) after chemotherapy progression, but conversely associated improved disease control 0.045) ICI-treated, PD-L1 high first-line AXL+ immune-cell infiltration total overall outcomes (PFS: 0.044, OS: 0.054). AXL-upregulation showed enrichment mutations PD-L1-upregulation ICI-response such as MUC4 ZNF469 , well adverse CSMD1 LRP1B which an immune-suppressed tumor phenotype poor ICI prognosis particularly within chemotherapy-treated burden had no effect on ICI-outcomes was a lack tumor-infiltrating immune cells. Spatial-immunophenotyping provided evidence that tumor-cell modulate the microenvironment favor infiltrating, activated neutrophils over anti-tumor immune-subsets CD4 CD8 T-cells. Conclusion distinct oncotypes microenvironmental immune-profiles define chemotherapy-induced ICI-resistance, suggests combination inhibitors current chemoimmunotherapy regimens can benefit