Remodeling of tumor microenvironments by EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer
Soo-Min Kim, Jaemoon Koh, Tae Min Kim, Songji Oh, Soyeon Kim, Jeonghwan Youk, Miso Kim, Bhumsuk Keam, Yoon Kyung Jeon, Dong‐Wan Kim, Dae Seog Heo
Abstract
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.