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

Abstract

Immune-checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death-1-ligand 1 (PD-L1) have become new treatment options for various malignancies. ICIs bind to immune-checkpoint inhibitory receptors or to the foregoing ligands and block inhibitory signals to release the brakes on the immune system, thereby enhancing immune anti-tumor responses. On the other hand, unlike conventional chemotherapies, ICIs can cause specific side effects, called immune-related adverse events (irAEs). These toxicities may affect various organs, including the lungs. ICI-related pneumonitis (ICI-pneumonitis) is not the most frequent adverse event, but it is serious and can be fatal. In this review, we summarize recent findings regarding ICI-pneumonitis, with a focus on potential pathogenesis and treatment.

Keywords: immune checkpoint; immune-checkpoint inhibitor-related pneumonitis; immune-related adverse events (irAEs).

Figure 1

Possible pathobiological mechanisms underlying immune-checkpoint inhibitor-related pneumonitis. Cellular immunity mediated by T cells is thought to be highly involved. T-cell-dominated lymphocytosis is present in BALF from ICI-pneumonitis. CD8+ T cells in BALF express immune-checkpoint proteins (PD-1+TIM-3+), characteristic of tumor-infiltrating T lymphocytes. A substantial number of T cell clones in BALF were identical with T cells in the peritumoral lesion. These facts support the hypothesis that ICI-pneumonitis may be induced by ICI-activated T cells recognizing self-peptides or shared epitopes between tumors and the lungs. Moreover, the proportion of PD-1+PD-L1+ cells among CD8+ T cells in BALF was correlated with the severity of ICI-pneumonitis by anti-PD-1 therapies, suggesting that the disruption of cis-PD-1/PD-L1 regulation by anti-PD-1/PD-L1 therapies can induce aberrant activation of self-reacting T cells, resulting in severe ICI-pneumonitis. Autoantibodies such as anti-CD74 antibodies may also be involved in the pathogenesis of ICI-pneumonitis.

Figure 2

Radiologic features of immune-checkpoint inhibitor-related pneumonitis. (A) Organizing pneumonia (OP) pattern in a patient with stage IV renal cell carcinoma treated with nivolumab. An axial chest CT image obtained 4 months after nivolumab therapy shows an infiltration shadow on the peripheral pleural side, predominantly in the lower lung field. (B) A nonspecific interstitial pneumonia (NSIP) pattern in a patient with stage IV bladder cancer treated with nivolumab. An axial chest CT image obtained 11 months after nivolumab therapy shows bilateral lower lobe ground-glass opacities and reticular opacities with regions of subpleural sparing. (C) A hypersensitivity pneumonitis (HP) pattern in a patient with stage IV lung adenocarcinoma treated with pembrolizumab. An axial chest CT image obtained 5 months after pembrolizumab therapy shows diffuse, subtle ground-glass opacities. (D) A diffuse alveolar damage (DAD) pattern in a patient with stage IV lung adenocarcinoma treated with pembrolizumab. An axial chest CT image obtained 5 months after pembrolizumab therapy shows diffuse ground-glass opacities and consolidation. All images were collected at Kyushu University.