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

Front Immunol. 2024 Aug 21:15:1444007. doi: 10.3389/fimmu.2024.1444007. eCollection 2024.

Abstract

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.

Keywords: AXL receptor tyrosine kinase; NSCLC; biomarker; immunotherapy resistance; tumor microenvironment.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Axl Receptor Tyrosine Kinase*
  • Biomarkers, Tumor
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / immunology
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Humans
  • Immune Checkpoint Inhibitors* / therapeutic use
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / immunology
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Male
  • Middle Aged
  • Mutation
  • Proto-Oncogene Proteins* / genetics
  • Receptor Protein-Tyrosine Kinases* / genetics
  • Treatment Outcome
  • Tumor Microenvironment* / immunology

Substances

  • Axl Receptor Tyrosine Kinase
  • Receptor Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins
  • Immune Checkpoint Inhibitors
  • AXL protein, human
  • Biomarkers, Tumor

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. FG received funding from a Helse-Vest research scholarship, AR was supported by the Norwegian Research Council industrial PhD scheme (grant number 311397). The authors declare that this study received funding from BerGenBio ASA through their contribution to the Industrial PhD fellowship of AR. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.