Remodeling of tumor microenvironments by EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer
Soomin 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
Affiliations
Soomin Kim
Cancer Research Institute, Seoul National University, Seoul, Republic of Korea; Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, Republic of Korea
Jaemoon Koh
Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
Tae Min Kim
Cancer Research Institute, Seoul National University, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; Corresponding author
Songji Oh
Cancer Research Institute, Seoul National University, Seoul, Republic of Korea; Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, Republic of Korea
Soyeon Kim
Cancer Research Institute, Seoul National University, Seoul, Republic of Korea
Jeonghwan Youk
Cancer Research Institute, Seoul National University, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
Miso Kim
Cancer Research Institute, Seoul National University, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
Bhumsuk Keam
Cancer Research Institute, Seoul National University, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
Yoon Kyung Jeon
Cancer Research Institute, Seoul National University, Seoul, Republic of Korea; Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
Dong-Wan Kim
Cancer Research Institute, Seoul National University, Seoul, Republic of Korea; Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
Dae Seog Heo
Cancer Research Institute, Seoul National University, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
Summary: 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.
