AXL Targeting Overcomes Human Lung Cancer Cell Resistance to NK- and CTL-Mediated Cytotoxicity

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Tumorigenesis involves genetic instability and heterogeneity, leading to immune resistance.
• Hypoxia and resistance mechanisms promote cancer cell plasticity, impacting treatment efficacy.
• AXL receptor tyrosine kinase is implicated in cancer cell plasticity and drug resistance.

Purpose of the Study:

• To investigate the role of AXL in immune resistance within lung cancer.
• To explore AXL's involvement in hypoxia-induced tumor plasticity and its effect on immune cell-mediated killing.
• To identify AXL-mediated molecular pathways contributing to immune escape in non-small cell lung cancer (NSCLC).

Main Methods:

• Studied human lung cancer clones with mesenchymal or epithelial features derived from hypoxia-induced plasticity models.
• Assessed AXL expression and its correlation with resistance to natural killer (NK) and cytotoxic T lymphocyte (CTL) killing.
• Utilized a small-molecule AXL inhibitor and analyzed downstream molecular networks (NF-κB, ICAM1, ULBP1, MAPK).

Main Results:

• AXL expression was elevated in mesenchymal lung cancer clones, correlating with increased resistance to NK and CTL-mediated killing.
• AXL inhibition sensitized mesenchymal lung cancer cells to cytotoxic lymphocyte-mediated killing.
• AXL-dependent immune resistance involved NF-κB activation, increased ICAM1 and ULBP1 expression, and MAPK inhibition.

Conclusions:

• AXL plays a significant role in mediating immune escape in lung cancer through a defined molecular pathway.
• AXL is a potential biomarker for predicting tumor resistance to NK and CTL immunity in NSCLC.
• Targeting AXL presents a therapeutic strategy to enhance anti-tumor immune responses in NSCLC patients.