Involvement of Naïve CD4+ T cells in the Pathogenesis of Osimertinib-induced Pneumonitis

Background: Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has exhibited significant efficacy in the treatment of EGFR-mutated non-small cell lung cancer. Drug-induced interstitial lung disease is a potentially fatal complication of osimertinib therapy. Although there is often an elevated number of lymphocytes in the bronchoalveolar lavage fluid (BALF) in patients with drug-induced pneumonitis, the precise involvement of lymphocytes in osimertinib-induced pneumonitis remains unclear. Therefore, we investigated the pathogenesis of osimertinib-induced pneumonitis using BALF obtained from patients with osimertinib-induced pneumonitis and a mouse model of osimertinib-induced pneumonitis. Methods: Mass cytometry was used to analyze BALF cells obtained from patients with osimertinib-induced pneumonitis. A mouse model of osimertinib-induced pneumonitis was established by the administration of naphthalene and osimertinib. Histopathological evaluation, body weight measurements, BALF analysis, and RNA sequencing were performed to investigate immune cell involvement and the mechanisms underlying osimertinib-induced pneumonitis. Results: Analysis of BALF cells obtained from patients with osimertinib-induced pneumonitis revealed the expansion of CCR7+ CD45RA+ naïve T cells. In the mouse model, osimertinib administration following naphthalene-induced club cell injury exacerbated lung inflammation, leading to increased inflammatory cell infiltration and body weight loss. BALF analysis revealed elevated proportions of T cells, including CD4+ and double-negative T cells, in mice administered osimertinib after naphthalene treatment. Bulk RNA sequencing identified upregulation of chemokine-related biological processes, with increased the expression of C-C motif chemokine ligand 21 (Ccl21) and C-C motif chemokine ligand 8 (Ccl8) in lung tissue, and immunostaining confirmed elevated expression of Ccl21 and Ccl8 in the distal bronchiolar epithelium. Conclusion: This study provides insights into the immune mechanisms underlying osimertinib-induced pneumonitis, which are crucial for overcoming this fatal complication in EGFR-positive non-small cell lung cancer.