TH1/17 hybrid CD4+ cells in bronchial alveolar lavage fluid from leukemia patients with checkpoint inhibitor-induced pneumonitis.

Abstract

204 Background: Immune checkpoint inhibitor (ICI)-based therapies are showing encouraging results for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). 20% of AML or MDS patients receiving an ICI develop lung inflammation (herein, pneumonitis), one of fatal immune related adverse events (irAEs). The mechanisms of pneumonitis, the most important step for risk stratification and early detection, remain elusive. Methods: We analyzed bronchial alveolar lavage (BAL) fluid from 8 AML or MDS patients, who received an ICI, developed respiratory symptoms, and underwent a standard-of-care bronchoscopy. As a control, we analyzed BAL fluid from 5 AML or MDS patients who had never received an ICI or had received last ICI more than 16 weeks prior to the bronchoscopy. We also analyzed matched blood within 72 hours after the bronchoscopy. We stained CD4+ cells with lineage specific markers, including CXCR3, CXCR5, CD25, CD127, CCR4, and CCR6. Proportion of the CD4+ cell subsets within total CD4+ lymphocytes in BAL and blood were compared between the pneumonitis and controls. Results: Th1 (CXCR3hi) CD4+ cells were expanded in controls in BAL (pneumonitis versus control, 4.2 ± 2.5 % versus 17.2 ± 6.3 % within total CD4+ lymphocytes, P= 0.04) and blood (pneumonitis versus control, 0.5 ± 0.3 % versus 4.0 ± 1.3 % within total CD4+ lymphocytes, P= 0.01). In contrast, Th1/17 (CXCR3hi CCR6hi) hybrid CD4+ cells, known to be pathogenic in autoimmune diseases, were expanded in BAL from the pneumonitis group (pneumonitis versus control, 40.3 ± 8.4 % versus 13.7 ± 4.5 % within total CD4+ lymphocytes, P= 0.03). Th1/17 hybrid CD4+ cells were also PD-1hi Ki67hi, suggesting their hyperactive status. Though not reached statistical significance, regulatory T cells were decreased in BAL from pneumonitis group (pneumonitis versus control, 20.8 ± 4.9 % versus 26.2 ± 9.2 % within total CD4+ lymphocytes). Conclusions: These results suggest that Th1/17 hybrid CD4+ cells may play a central role in pneumonitis. Understanding of the Th1/17 hybrid CD4+ cell biology will provide therapeutic targets and reliable biomarkers for pneumonitis.