CXCR2 inhibition as a candidate for immunomodulation in the treatment of K-RAS-driven lung adenocarcinoma

Background: Lung adenocarcinoma (LUAD) is the predominant histologic subtype of primary lung cancer. Although driver mutations in the Kirsten rat sarcoma 2 viral oncogene homolog (K-RAS) oncogene occur in a quarter of LUAD cases, this alteration portends a poor prognosis and lacks dedicated therapeutics. The C-X-C motif chemokine receptor 2 (CXCR2) mediates neutrophil egress from bone marrow. Neutrophils are thought to exert immunosuppressive effects in the tumour immune microenvironment (TIME) of lung cancer. We found that CXCR2 ligand expression is preferentially upregulated in K-RAS-driven LUAD. K-RAS is a commonly tested oncogene during the diagnostic work-up of LUAD and may serve as a surrogate marker for the utility of CXCR2 inhibition either alone or in combination with other active systemic therapies. Methods and results: We utilized the PRECOG data set of cancer gene expression and survival outcome data to show that CXCR2 expression is at least 18-fold greater in neutrophils than other immune cells in LUAD. Overexpression of 8 out of the 9 known CXCR2 ligands in LUAD correlates with poorer survival outcomes (p < 0.05) (PRECOG). In addition, high neutrophil infiltration is associated with the poorest survival compared with other immune infiltrates (p < 0.001) (PRECOG). Infiltrating neutrophils in a 100-patient LUAD tissue microarray are associated with worse overall survival (p < 0.05). Neutrophil migration to K-RAS, EGFR, ALK and ROS1-driven LUAD cell lines in microfluidic devices modelling the CXCR2 axis ex vivo was highest in K-RAS-driven LUAD. CXCR2 inhibition reduced neutrophil migration only in K-RAS-driven LUAD (p < 0.05). K-RAS comutational status with TP53 affects neutrophil recruitment capabilities of LUAD cell lines, which is also reversible via CXCR2 inhibition (p < 0.05). Conclusion: K-RAS-driven LUAD is a promising candidate for effective inhibition of neutrophil migration and may potentiate existing systemic therapies.