Remodeling of tumor microenvironments by EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer

Patients with EGFR mutations exhibit immunosuppressive microenvironments, limiting responsiveness to immunotherapy. We used digital spatial profiling to analyze non-small cell lung carcinomas in 25 patients before and after EGFR tyrosine kinase inhibitor (TKI) treatment, including 14 patients treated with first-line osimertinib, focusing on CD45-positive immune regions and pan-cytokeratin-positive tumor regions. Osimertinib treatment resulted in altered angiogenic pathways and immune cell proportions, with reduced plasma cells (22.2%-11.7%; p = 0.025) and increased macrophage infiltration (p = 0.145). The most predominant immune subtypes before and after treatment was the interferon-γ (IFN-γ)-dominant C2 subtype and the lymphocyte-depleted C4 subtype. Two patients who showed the opposite pattern, transiting from C4 to C2, had durable responses to subsequent atezolizumab/bevacizumab/carboplatin/paclitaxel treatment. Our results shed light on the immunomodulatory effects of osimertinib treatment and suggest that co-targeting angiogenesis and anti-programmed death (ligand) 1 might be effective in EGFR-TKI-resistant non-small cell lung cancer.