Immune-checkpoint profiles for T cells in bronchoalveolar lavage fluid of patients with immune-checkpoint inhibitor-related interstitial lung disease

Abstract

Immune-checkpoint inhibitors (ICIs) have improved clinical outcomes and are becoming a standard treatment for many cancer types. However, these drugs also induce immune-related adverse events, among which interstitial lung disease (ILD) is potentially fatal. The underlying mechanism of ILD induction by ICIs is largely unknown. With the use of flow cytometry, we determined the expression levels of the immune-checkpoint proteins PD-1, TIM-3, TIGIT, LAG-3 and PD-L1 in T cells of bronchoalveolar lavage fluid (BALF) from patients with ICI-related ILD and compared them with those for patients with sarcoidosis or with ILD related to connective tissue disease or cytotoxic drug use. The proportions of CD8+ T cells positive for both PD-1 and TIM-3 or for TIGIT in BALF were significantly higher for ICI-related ILD patients than for those with other types of ILD. A prominent increase in the proportion of PD-1+PD-L1+ cells among CD8+ T cells was also apparent in BALF of a patient with a fatal case of ICI-related ILD, and the proportion of such cells was positively correlated with the grade of ICI-related ILD. Our data reveal the immune-checkpoint profiles of T cells in ICI-related ILD and may provide mechanistic insight into the development of this adverse event.

Insights into Potential Pathogenesis and Treatment Options for Immune-Checkpoint Inhibitor-Related Pneumonitis

“…The DAD pattern is characterized by scattered or diffuse areas of groundglass opacities with or without traction bronchiectasis. In our study, 77% OP, 15% HP, and 7.7% NSIP patterns were observed among 13 cases of ICI-pneumonitis [24]. Nishino et al reported 20 cases of ICI-pneumonitis in 10 trials of nivolumab imaging with the following rates: 65% OP, 15% NSIP, 10% HP, and 10% DAD [54].…”

“…We previously reported that T-cell-dominated lymphocytosis is evident in bronchoalveolar lavage fluid (BALF) from ICI-pneumonitis [23,24], which is consistent with other case series [25][26][27]. Proportions of CD8 + T cells expressing immunecheckpoint proteins (CD8 + PD-1 + TIM-3 + ), characteristic of tumor-infiltrating T lymphocytes (TILs) [28], are higher in ICI-pneumonitis than in other ICI-associated causes [23,24,29]. These observations suggest that TILs may contribute to the pathogenesis of ICI-ILD.…”

“…Intriguingly, the proportion of PD-1 + PD-L1 + cells among CD8 + T cells in BALF was correlated with the severity of ICI-pneumonitis [24]. Recent studies revealed that antigenpresenting, cell-intrinsic PD-1 or CD80 interacts with PD-L1 in cis (on the same cell surface) to inhibit PD-1 signaling in T cells [32,33].…”

Imaging Changes and Immune-Checkpoint Expression on T Cells in Bronchoalveolar Lavage Fluid from Patients with Pulmonary Sarcoidosis

“…Flow cytometry was performed as described previously [ 11 ]. Briefly, BALF was filtered through a mesh to remove debris and centrifuged to isolate cells.…”

Differentiation of COVID-19 Pneumonitis and ICI Induced Pneumonitis

“…Using bronchoscopy, a deep sputum sample can be collected, which is reliable for elimination of the differential diagnosis of infection and guidance of antimicrobial therapy (21). In ICI pneumonitis, BAL fluid often show lymphocytic inflammation of alveoli with an increased proportion of lymphocytes in the cell count [normal lymphocyte count ≈11%, in ICI pneumonitis ≈37% (22,23)]. Transbronchial biopsies during bronchoscopy can be considered and may be helpful to make the diagnosis (24).…”