Elevated levels of IL‑17A and IL‑35 in plasma and bronchoalveolar lavage fluid are associated with checkpoint inhibitor pneumonitis in patients with non‑small cell lung cancer

Abstract

Advances in the immunology have identified that interleukin (IL)-17 and IL-35 are cytokines with diverse functions, serving important roles in autoimmune diseases and chronic inflammation. Checkpoint inhibitor pneumonitis (CIP) is focal or diffuse lung inflammation induced by immune checkpoint inhibitors and the underlying pathogenesis has not been fully explored. The aim of the present study was to investigate the roles of IL-17A and IL-35, and the correlation between their levels and different T cell subsets in CIP. The levels of IL-17A and IL-35 in peripheral blood and bronchoalveolar lavage fluid (BALF) were measured in patients with non-small cell lung cancer (NSCLC) with CIP, and the corresponding controls. The percentages of helper T lymphocyte (Th)1, Th2 and Th17 cells, and regulatory T cells (Tregs) in the peripheral blood were synchronically detected. Serum levels of IL-17A and IL-35 were significantly increased at the time of CIP diagnosis compared with the baseline, and significantly decreased upon clinical recovery or improvement. IL-17A and IL-35 were also increased in the BALF during the development of CIP compared with the baseline. Serum levels of IL-17A were positively correlated with the percentages of Th1 and Th17 cells as well as the ratio of Th17 to Tregs, but negatively associated with the frequency of Tregs in CIP. Serum levels of IL-35 were positively correlated with the percentages of Th1 and Tregs, and with the ratio of Th1 to Th2 cells in CIP. A higher frequency of Th1 and Th17 cells, as well as higher ratios of Th17 to Tregs and Th1 to Th2 cells were detected upon development of CIP comparing with the baseline. These data suggested that the activation of Th1 and Th17 cells, as well as Treg inhibition contributed to the imbalanced ratios of Th1 to Th2 and Th17 to Tregs, which resulted in increased secretion of IL-17A and IL-35 in the plasma and BALF; this may present a valuable index to monitor the development and severity of CIP in patients with NSCLC receiving immunotherapy.

Immune Checkpoint Inhibitor-Associated Pneumonitis in Non-Small Cell Lung Cancer: Current Understanding in Characteristics, Diagnosis, and Management

“…In clinical trial data (10,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44), the incidence of CIP for all grades was approximately 2% to 38%, and incidence for grade ≥ 3 CIP was approximately 0.6% to 2.7%. In real-world data, the incidence of CIP in patients with NSCLC was 4.8% to 39.3% (18,24,27,28,(45)(46)(47)(48)(49)(50)(51)(52). The discrepancy between data from these two sources might be partly attributed to the increasing awareness of CIP in the medical community, which contributed to more frequent clinical detection and less stringent inclusion criteria for real-world studies compared with randomized trials.…”

IL-35 Regulates the Function of Immune Cells in Tumor Microenvironment

“…Checkpoint inhibitor pneumonia (CIP) is a particularly dangerous form of immune-related adverse events (IrAE) that can arise in NSCLC patients receiving anti-PD-1/PD-L1 therapy (104,105). Wang et al discovered that the occurrence of CIP changes the proportion of T cell subsets in plasma, thereby promoting increased secretion of IL-35 in plasma and BALF (106). As such, measuring IL-35 levels may offer insight into the risk of developing CIP, and IL-35 may also represent a viable therapeutic target in patients undergoing tumor immunotherapy.…”

Immune Checkpoint Inhibitor-Related Pneumonitis

“…In cases of clinical and radiologic doubt, bronchoscopy with BAL could help to rule out competing diagnoses, such as infections [88]. Also, the identification of biomarkers in BAL, which could indicate the occurrence of ICI-related pneumonitis is under research; recently, elevated levels of interleukin-17A and interleukin-35 were associated with the development and severity of ICI-related pneumonitis [89]. Concerning lung biopsy, on the one hand, it may help to support an alternative diagnosis, such as lymphangitis carcinomatosa, but on the other hand, there is no specific pathology associated with ICI-related pneumonitis; its histological features may involve diffuse alveolar damage syndrome, non-specific interstitial pneumonitis, HP-like changes, and OP pattern of changes [86].…”