Immune checkpoints in chronic obstructive pulmonary disease

Abstract

Cell-mediated immune responses are vital to the body's defence against infection and play a key role in tumour immunity. T-cell activation and cytotoxic function is tightly regulated by a series of immune-regulatory receptor-ligand interactions or immune checkpoints. These controls limit immune-mediated damage, particularly in the context of chronic infection. However, prolonged signalling through these axes can lead to progressive loss of T-cell function, termed exhaustion.Understanding of the biology of checkpoints and that exhaustion is reversible has been key to the development of new therapies directed at reversing the dysfunctional status of T-cells, which are dramatically improving outcomes of cancer treatment.Emerging data suggest that immune checkpoint axes are dysregulated in chronic obstructive pulmonary disease (COPD). T-cells from diseased lungs express the key receptor programmed death (PD)1 and demonstrate loss of cytotoxic function. However, the picture is complex with evidence of downregulation of the associated ligand PDL1 on alveolar macrophages. The resulting impact may be excessive T-cell inflammation as a consequence of acute infection, which may contribute to the pattern of exacerbation and lung damage characteristic of COPD. More work is needed to understand these immune controls in COPD before the therapeutic advances seen in lung cancer can be explored.

Checkpoint Inhibitor Pneumonitis: Too Clinically Serious For Benefit?

“…COPD features dysregulated immune checkpoint axes. 30 Relative to healthy subjects, patients with COPD show attenuated programmed death ligand 1 expression on alveolar macrophages in response to viral infections and elevated interferon-g release. 31 This milieu of immune dysregulation may predispose the chronically inflamed COPD lung to more frequent and higher grade pneumonitis.…”

Chronic Obstructive Pulmonary Disease and Lung Cancer: Underlying Pathophysiology and New Therapeutic Modalities

“…As immunotherapies can modulate T-cell response via inhibition of immune checkpoints, they may be of potential therapeutic value for COPD. There are emerging data suggesting a potential role of dysregulated immune checkpoints leading to excessive T cell response in COPD [103].…”

Lymphatic Pump Manipulation in Patients with Chronic Obstructive Pulmonary Disease

“…The speed of the lymphatic flow is approximately 125 mL/h in a person at rest but can increase by a factor of 10 during active movements [12][13]. Another passive mechanism that can manage lymphatic flow is oxygen pressure, particularly at low gradients (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40); if the oxygen pressure is higher, the lymphatic flow slows down. Temperature can also influence the speed of the lymphatic flow; the function of the lymphatic system is optimal at temperatures ranging between 32°C and 37°C, and probably acts via extracellular osmotic changes.…”

“…Another signal of the constant activation of T lymphocytes and the generally inflammatory status is the reduction in function and quantity of some receptors. T lymphocytes have receptors known as "receptor programmed death" type 1 (PD1) which regulate the half-life of lymphocytes [36]. Studies have shown that the enlargement and neoformation of the lymphatic nodes and vessels reflect the severity of pathology in patients with COPD; there is a close relationship between COPD and pulmonary lymphatic system dysfunction [1,19,[37][38].…”