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Modulation of the PD-1/PD-L1 immune checkpoint axis during inflammation-associated lung tumorigenesis.

ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a significant risk factor for lung cancer. One potential mechanism through which COPD contributes to lung cancer development could be through generation of an immunosuppressive microenvironment that allows tumor formation and progression. In this study, we compared the status of immune cells and immune checkpoint proteins in lung tumors induced by the tobacco smoke carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) or NNK + lipopolysaccharide (LPS), a model for COPD-associated lung tumors. Compared with NNK-induced lung tumors, NNK+LPS-induced lung tumors exhibited an immunosuppressive microenvironment characterized by higher relative abundances of PD-1+ tumor-associated macrophages, PD-L1+ tumor cells, PD-1+ CD4 and CD8 T lymphocytes and FOXP3+ CD4 and CD8 T lymphocytes. Also, these markers were more abundant in the tumor tissue than in the surrounding 'normal' lung tissue of NNK+LPS-induced lung tumors. PD-L1 expression in lung tumors was associated with IFNγ/STAT1/STAT3 signaling axis. In cell line models, PD-L1 expression was found to be significantly enhanced in phorbol-12-myristate 13-acetate activated THP-1 human monocytes (macrophages) treated with LPS or incubated in conditioned media (CM) generated by non-small cell lung cancer (NSCLC) cells. Similarly, when NSCLC cells were incubated in CM generated by activated THP-1 cells, PD-L1 expression was upregulated in EGFR- and ERK-dependent manner. Overall, our observations indicate that COPD-like chronic inflammation creates a favorable immunosuppressive microenvironment for tumor development and COPD-associated lung tumors might show a better response to immune checkpoint therapies.

SUBMITTER: Narayanapillai SC

PROVIDER: S-EPMC8241221 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Blocking the interaction between the programmed cell death (PD)-1 protein and one of its ligands, PD-L1, has been reported to have impressive antitumor responses. Therapeutics targeting this pathway are currently in clinical trials. Pembrolizumab and nivolumab are the first of this anti-PD-1 pathway family of checkpoint inhibitors to gain accelerated approval from the US Food and Drug Administration (FDA) for the treatment of ipilimumab-refractory melanoma. Nivolumab has been associated with improved overall survival compared with dacarbazine in patients with previously untreated wild-type serine/threonine-protein kinase B-raf proto-oncogene BRAF melanoma. Although the most mature data are in the treatment of melanoma, the FDA has granted approval of nivolumab for squamous cell lung cancer and the breakthrough therapy designation to immune- checkpoint inhibitors for use in other cancers: nivolumab, an anti-PD-1 monoclonal antibody, for Hodgkin lymphoma, and MPDL-3280A, an anti-PD-L1 monoclonal antibody, for bladder cancer and non-small cell lung cancer. Here we review the literature on PD-1 and PD-L1 blockade and focus on the reported clinical studies that have included patients with melanoma.PubMed was searched to identify relevant clinical studies of PD-1/PD-L1-targeted therapies in melanoma. A review of data from the current trials on clinicaltrial.gov was incorporated, as well as data presented in abstracts at the 2014 annual meeting of the American Society of Clinical Oncology, given the limited number of published clinical trials on this topic.The anti-PD-1 and anti-PD-L1 agents have been reported to have impressive antitumor effects in several malignancies, including melanoma. The greatest clinical activity in unselected patients has been seen in melanoma. Tumor expression of PD-L1 is a suggestive, but inadequate, biomarker predictive of response to immune-checkpoint blockade. However, tumors expressing little or no PD-L1 are less likely to respond to PD-1 pathway blockade. Combination checkpoint blockade with PD-1 plus cytotoxic T-lymphocyte antigen (CTLA)-4 blockade appears to improve response rates in patients who are less likely to respond to single-checkpoint blockade. Toxicity with PD-1 blocking agents is less than the toxicity with previous immunotherapies (eg, interleukin 2, CTLA-4 blockade). Certain adverse events can be severe and potentially life threatening, but most can be prevented or reversed with close monitoring and appropriate management.This family of immune-checkpoint inhibitors benefits not only patients with metastatic melanoma but also those with historically less responsive tumor types. Although a subset of patients responds to single-agent blockade, the initial trial of checkpoint-inhibitor combinations has reported a potential to improve response rates. Combination therapies appear to be a means of increasing response rates, albeit with increased immune-related adverse events. As these treatments become available to patients, education regarding the recognition and management of immune-related effects of immune-checkpoint blockade will be essential for maximizing clinical benefit.

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Modulation of the PD-1/PD-L1 immune checkpoint axis during inflammation-associated lung tumorigenesis.

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