Checkpoint Inhibitor Pneumonitis Induced by Anti-PD-1/PD-L1 Therapy in Non-Small-Cell Lung Cancer: Occurrence and Mechanism

Abstract

Immune checkpointty inhibitors (ICIs), particularly those targeting programmed death 1 (PD-1) and anti-programmed death ligand 1 (PD-L1), enhance the antitumor effect by restoring the function of the inhibited effector T cells and produce durable responses in a large variety of metastatic and late patients with non-small-cell lung cancer. Although often well tolerated, the activation of the immune system results in side effects known as immune-related adverse events (irAEs), which can affect multiple organ systems, including the lungs. The occurrence of severe pulmonary irAEs, especially checkpoint inhibitor pneumonitis (CIP), is rare but has extremely high mortality and often overlaps with the respiratory symptoms and imaging of primary tumors. The development of CIP may be accompanied by radiation pneumonia and infectious pneumonia, leading to the simultaneous occurrence of a mixture of several types of inflammation in the lungs. However, there is a lack of authoritative diagnosis, grading criteria and clarified mechanisms of CIP. In this article, we review the incidence and median time to onset of CIP in patients with non-small-cell lung cancer treated with PD-1/PD-L1 blockade in clinical studies. We also summarize the clinical features, potential mechanisms, management and predictive biomarkers of CIP caused by PD-1/PD-L1 blockade in non-small-cell lung cancer treatment.

Keywords: checkpoint inhibitor pneumonitis; immune checkpoint inhibitors; immune-related adverse events; non-small-cell lung cancer; programmed cell death 1; programmed cell death ligand 1.

Figure 1

Onset time of checkpoint inhibitor pneumonitis (CIP) in NSCLC patients receiving PD-1/PD-L1 treatment. NSCLC, non-small-cell lung cancer. The curve in the figure does not represent the change in the incidence of CIP over time. The abscissa of the highest point of the curve represents the median time of CIP reported in the studies (16, 18, 34, 35, 37).

Figure 2

The potential mechanisms of checkpoint inhibitor pneumonitis (CIP) in NSCLC patients receiving PD-1/PD-L1 inhibitor monotherapy. The occurrence of checkpoint inhibitor pneumonitis (CIP) in NSCLC is the result of a combination of many factors. Blockade of the PD-1-PD-L1 pathway by PD-1/PD-L1 mAbs (PD-1 mAb in the figure, for example) will upregulate and promote Th1 and Th17 cells and downregulate and inhibit Th2 cells and Tregs. Without immunosuppression of Th2 cells and Tregs, excessive immune responses and cytokine secretion of Th1 and Th17 cells will cause autoimmune damage in normal tissues such as the lung. In addition, autoantibodies increased after PD-1/PD-L1 blockade can also cause normal tissue lesions. Proinflammatory cytokines secreted by activated T cells promote the infiltration of inflammatory cells. Under the stimulation of IL-6, CRP produced by the liver will promote inflammation and strengthen autoimmunity. Through the “gut-lung axis”, gut microbiomes can regulate the immune microenvironment in the lung. Overall, the immune dysregulation caused by PD-1/PD-L1 blockade leads to the occurrence and development of CIP. NSCLC, non-small cell cancer; CIP, checkpoint inhibitor pneumonitis; PD-1, programmed cell death protein 1; PD-L1, programmed cell death protein ligand-1; mAbs, monoclonal antibody; Th, helper T cell; IL, Interleukin; CRP, C-reactive protein.

Figure 3

Schematic diagram of the difference in the mechanism of CIP mediated by PD-L1 inhibitor and PD-1 inhibitor monotherapy. The mechanisms of checkpoint inhibitor pneumonitis (CIP) induced by PD-1 inhibitors and PD-L1 inhibitors in patients with NSCLC are not completely the same and may be related to PD-1 ligands, including PD-L1 and PD-L2. PD-L1 blockade does not influence the binding between PD-L2 and its receptor PD-1, which is associated with immune tolerance in lung tissue. PD-1 inhibitors can simultaneously block the interaction between PD-1 and its ligands, including PD-L1 and PD-L2. The blockade of PD-1-PD-L2 signaling by PD-1 inhibitors has been observed to increase cytokine production and/or CD4+ T cell proliferation, which can increase the incidence and severity of CIP compared with PD-L1 inhibitors. Moreover, the application of a PD-1 inhibitor can increase the binding of PD-L2 to repulsive guidance molecule b (RGMb). RGMb has been observed to be expressed in lung interstitial macrophages, alveolar epithelial cells and other cells of the immune system. The interaction of RGMb–PD-L2 can increase T cell activity to self-antigens by increasing the clonal expansion of T cells that reside in the lung and then damage normal lung tissue. NSCLC, non-small cell cancer; CIP, checkpoint inhibitor pneumonitis; PD-1, programmed cell death protein 1; PD-L1, programmed cell death protein ligand-1; PD-L2, programmed cell death protein ligand-2; RGMb, repulsive guidance molecule b.