Reply: The PD-1–PD-L1 Axis in Chronic Obstructive Pulmonary Disease

Staples, Karl J.; Wilkinson, Tom

doi:10.1164/rccm.201604-0863le

Cited by 3 publications

(6 citation statements)

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“…There is also evidence that the activation of the PD-1/PD-L1 axis is implicated in the pathogenesis of COPD (7)(8)(9). Thus, it is a matter of discussion whether the PD-1 pathway contributes to the development of COPD and whether therapeutic antibodies against PD-1 are effective in patients with COPD, even though the suggested mechanisms by which anti-PD-1/PD-L1 therapies result in decreased tumor burden, such as neoantigen-specific T cell responses, do not seem to be relevant in cancer-free patients with COPD (9,10,25). Therefore, and as experimental studies examining the role of PD-1/PD-L1 axis in preclinical COPD models are lacking, we decided to study the role of PD-1 in CS-and NTHi-dependent preclinical models.…”

Section: Discussionmentioning

confidence: 99%

“…However, it is mostly unknown whether or not the PD-1/PD-L1 axis has a function in the development and pathogenesis of COPD and whether therapeutic modulation of the PD-1/ PD-L1 axis is beneficial or unfavorable for patients with COPD. As the activation of PD-1 may be a mechanism to avoid overstimulation by bacteria, it is possible that blocking of the PD-1/PD-L1 axis results in increased pulmonary inflammation and further exacerbates the disease (10,11). However, therapeutic antibodies against PD-1/PD-L1 have the potential to improve immunity against bacteria or viruses by reversing the suppression of T cells (10).…”

Section: Introductionmentioning

confidence: 99%

“…As the activation of PD-1 may be a mechanism to avoid overstimulation by bacteria, it is possible that blocking of the PD-1/PD-L1 axis results in increased pulmonary inflammation and further exacerbates the disease (10,11). However, therapeutic antibodies against PD-1/PD-L1 have the potential to improve immunity against bacteria or viruses by reversing the suppression of T cells (10). Thus, it is a matter of discussion whether and how therapeutic antibodies against PD-1 or PD-L1 affect the course of COPD (10,11).…”

Section: Introductionmentioning

confidence: 99%

“…However, therapeutic antibodies against PD-1/PD-L1 have the potential to improve immunity against bacteria or viruses by reversing the suppression of T cells (10). Thus, it is a matter of discussion whether and how therapeutic antibodies against PD-1 or PD-L1 affect the course of COPD (10,11).…”

Section: Introductionmentioning

confidence: 99%

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Blockade of PD-1 decreases neutrophilic inflammation and lung damage in experimental COPD

Ritzmann

Borchardt

Vella

et al. 2021

American Journal of Physiology-Lung Cellular and Molecular Phys

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Chronic obstructive lung disease (COPD) and lung cancer are both caused by smoking and often occur as comorbidity. The PD-1/PD-L1 axis is an important canonic immunoregulatory pathway and antibodies that specifically block PD-1 or PD-L1 have demonstrated efficacy as therapeutic agents for non-small cell lung cancer. The role of the PD-1/PD-L1 axis in the pathogenesis of COPD is unknown. Here, we analyzed the function of the PD-1/PD-L1 axis in preclinical COPD models and evaluated the concentrations of PD-1 and PD-L1 in human serum and bronchoalveolar lavage (BAL) fluids as biomarkers for COPD. Anti-PD-1 treatment decreased lung damage and neutrophilic inflammation in mice chronically exposed to cigarette smoke (CS) or Haemophilus influenzae (NTHi). Ex vivo stimulated macrophages obtained from anti-PD-1 treated mice released reduced amounts of inflammatory cytokines. PD-L1 concentrations correlated positively with PD-1 concentrations in human serum and BAL fluids. Lung sections obtained from COPD patients stained positive for PD-L1. Our data indicate that the PD-1/PD-L1 axis is involved in developing inflammation and tissue destruction in COPD. Inflammation-induced activation of the PD-1 pathway may contribute to disease progression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Blockade of PD-1 decreases neutrophilic inflammation and lung damage in experimental COPD

Ritzmann

Borchardt

Vella

et al. 2021

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Involvement of the PD-1 axis in COPD has recently been reported,22,35 suggesting the possibility that blocking the PD-1 axis may enhance lung inflammation in COPD patients, resulting in the deterioration of pulmonary physiology. However, this possibility has not yet been explored.…”

Section: Resultsmentioning

confidence: 98%

<p>Effect of PD-1 inhibitor on exhaled nitric oxide and pulmonary function in non-small cell lung cancer patients with and without COPD</p>

Suzuki

Inui

Karayama

et al. 2019

COPD

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BackgroundNivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor, has been shown to improve survival in non-small cell lung cancer (NSCLC). The possible involvement of PD-1 axis in the pathogenesis of inflammatory lung disease, such as chronic obstructive pulmonary disease (COPD) has also been reported. However, effects of PD-1 blockade on the respiratory system remain unknown.ObjectivesThis prospective study aimed to investigate whether inhibition of the PD-1 axis altered lung inflammation and pulmonary function in NSCLC patients with and without COPD.MethodThis was a prospective multi-center study. Measurements of fractioned exhaled nitric oxide (FeNO) and pulmonary function were performed before and after 4 cycles of nivolumab therapy.ResultsA total of 137 patients with NSCLC were initially enrolled, and subsequently 95 patients (41 COPD and 54 non-COPD) receiving 4 cycles of nivolumab administration were included. After anti-PD-1 therapy, FeNO levels were significantly elevated together with increase in peripheral eosinophils. Interestingly, significant FeNO elevation was only found in COPD patients without increased peripheral eosinophils, but this was not the case in non-COPD patients. Additionally, COPD patients exhibited significant increases in FVC and FEV1 but no changes in dyspnea scales, and acute exacerbation did not occur during the therapy.ConclusionOur observations suggest that anti-PD-1 therapy changed FeNO levels and pulmonary function in NSCLC patients. This therapy does not worsen COPD in terms of symptoms, pulmonary function, or acute exacerbation.

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Tumor necrosis correlates with PD-L1 and PD-1 expression in lung adenocarcinoma

et al. 2019

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Background: Predictive biomarkers for immunotherapy in lung cancer are intensively investigated; however, correlations between PD-L1/PD-1 expressions and clinical features or histopathological tumor characteristics determined on hematoxylin and eosin stained sections have not extensively been studied. Material and methods: We determined PD-L1 expression of tumor cells (TC) and immune cells (IC), and PD-1 expression of IC by immunohistochemistry in 268 lung adenocarcinoma (LADC) patients, and correlated the data with smoking, COPD, tumor grade, necrosis, lepidic growth pattern, vascular invasion, density of stromal IC, and EGFR/KRAS status of the tumors. Results: There was a positive correlation between PD-L1 expression of TC and IC, as well as PD-L1 and PD-1 expression of IC. Tumor necrosis was associated with higher PD-L1 expression of TC and PD-1 expression of IC. A negative correlation was observed between lepidic growth pattern and PD-L1 expression of TC and PD-L1/PD-1 expression of IC. EGFR mutation seemed to negatively correlate with PD-1 expression of IC, but this tendency could not be verified when applying corrections for multiple comparisons. No significant effect of the KRAS mutation on any of the studied variables could be established. Conclusion:Here we first demonstrate that the presence of necrosis correlates with higher PD-L1 expression of TC and PD-1 expression of IC in LADC. Further studies are required to determine the predictive value of this observation in LADC patients receiving immunotherapy.

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Reply: The PD-1–PD-L1 Axis in Chronic Obstructive Pulmonary Disease

Cited by 3 publications

References 6 publications

Blockade of PD-1 decreases neutrophilic inflammation and lung damage in experimental COPD

Blockade of PD-1 decreases neutrophilic inflammation and lung damage in experimental COPD

<p>Effect of PD-1 inhibitor on exhaled nitric oxide and pulmonary function in non-small cell lung cancer patients with and without COPD</p>

Tumor necrosis correlates with PD-L1 and PD-1 expression in lung adenocarcinoma

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