Background/Purpose:

Immune checkpoint inhibitor (ICI)-based combinations are showing encouraging results in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) treatment; however, ICIs can cause immune-related adverse events, inflammation of one or few organs. Ten percent of AML or MDS patients receiving an ICI develop respiratory complications, one of life-threatening immune related adverse events (irAEs) induced by ICIs. Understanding the mechanism by which pneumonitis occurs is important in risk stratification and early detection, however, this information remains elusive.

Methods: We performed flow cytometry and T cell receptor (TCR) analysis of cells isolated from bronchial alveolar lavage (BAL) fluid and matched blood from seven AML or MDS patients, who received ICI therapy, developed respiratory symptoms, and underwent a standard-of-care bronchoscopy (hereafter, ICI group). In parallel, we collected 22 BAL and matched blood samples from AML or MDS patients who had never been received an ICI. Six of these patients were determined to have documented bacterial or fungal pneumonia, based on the independent review of two independent pulmonologists and an infectious disease specialist, and served as controls.

Results:

The ICI group patients developed respiratory symptoms 42.6 ± 62.6 days (mean ± SD) after the first infusion of an ICI. TCR analysis showed that BAL T cells from the ICI group were clonally expanded compared to control BAL T cells. Immunophenotyping revealed that BAL CD8⁺ T cells in the ICI group were expanded (ICI vs. control, % within live lymphocytes, mean ± SD, 24.1 ± 18.3 vs. 5.8 ± 1.2, P = 0.02). These cells were most likely effector memory or terminally differentiated effector memory cells. Compared to BAL CD4⁺ T cells in controls, Th1.17 (CXCR3^hi CCR6^hi) CD4⁺ T cells, known to be implicated in autoimmune diseases, were expanded in the ICI group (% within live CD4⁺ T cells, 49.4 ± 19.5 vs. 16.8 ± 11.0, P = 0.03). IL-17 producing CD4⁺ T cells were also expanded in BAL in the ICI group (% within non-regulatory CD4⁺ T cells, 15.4 ± 4.8 vs. 7.6 ± 2.8, P = 0.03). Although statistical significance was not reached, Th17 cell-related cytokines were detected in BAL fluid in ICI group at a frequency similar to, or slightly greater than controls. Immunophenotypic characteristics of T cells in blood were comparable between the ICI group and control.

Conclusion:

These results suggest that Th1.17 CD4⁺ T cells may play a central role in ICI-associated pneumonitis. Understanding the biology of the Th1.17 CD4⁺ T cell will provide us therapeutic targets and reliable biomarkers of ICI-associated pneumonitis. Furthermore, characterization of Th1.17 CD4⁺ T cells may offer better insights into pneumonitis secondary to the autoimmune diseases.

« Back to 2018 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/immunophenotypic-analysis-of-t-cells-from-leukemia-patients-with-immune-checkpoint-inhibitor-associated-respiratory-complications/