Original ResearchHigh co-expression of PD-L1 and HIF-1α correlates with tumour necrosis in pulmonary pleomorphic carcinoma
Introduction
Pulmonary pleomorphic carcinoma (PPC) is rare, comprising 0.1–1.6% of all lung malignancies.[1], [2] In PPC, the giant cell and/or spindle cell elements comprising at least 10% of the tumour are admixed with components such as adenocarcinoma, squamous cell carcinoma, or undifferentiated non-small-cell carcinoma.[3], [4] PPC has a more aggressive clinical course than non-small-cell lung cancer (NSCLC), and its response to chemotherapy and radiotherapy is generally poor,[4], [5] although a few patients partially responded to gefitinib.[2], [6] Little is known about the biology of these neoplasms and the mechanism of chemoresistance or radioresistance and progression. Recent reports also described that PPC has a worse outcome than NSCLC, and systemic therapy needs to be explored.[4], [7]
A recently developed therapeutic strategy is the use of anti-tumour immunotherapy, such as blockade of co-inhibitory immune pathways, in particular programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) signalling. Aberrant activation of co-inhibitory pathways is a key determent of local immunosuppression, and counteracting PD-1/PD-L1 signalling was demonstrated to promote strong and durable tumour regression in several solid tumours with minimal immune-related adverse effects for patients with advanced cancer.[8], [9], [10] Clinical trials using monoclonal antibodies targeting the PD-1/PD-L1 axis revealed promising anti-tumour activity in several malignancies, including lung carcinoma. Preliminary data from these trials suggest that tumour PD-L1 expression may predict response to these treatments.[11], [12] However, the correlation of PD-L1 expression in tumour cells with treatment response of anti-PD-1 or PD-L1 therapy is still undetermined. In terms of Nivolumab, high PD-L1 expression was correlated with better treatment response in non-squamous NSCLC13 but not in squamous cell carcinoma.14 The results were also inconsistent in other phase I/II clinical trials using different agents of PD-1/PD-L1 blockade.[10], [15] Besides the role of predictive biomarker, PD-L1 shows inconsistent results among various studies as a prognostic biomarker.[11], [12], [16], [17], [18], [19], [20], [21], [22], [23] These conflicting results may be caused by different assays for immunohistochemical (IHC) staining of PD-L1 and various cutoff values. More than 20 IHC antibodies have been studied to represent lung cancer PD-L1 expression, but the standardisation of IHC testing and the validation of optimal IHC assays still need more works to clarify.24 Moreover, the heterogeneous histology, staging, treatment, and the driver mutations in these may also contribute to this complex scenario. Currently, a fully human anti-PD-1 antibody, Nivolumab, has yielded significant survival benefits in phase III trials of refractory NSCLC, either squamous14 or non-squamous histology,25 and became the recommended subsequent treatment for NSCLC patients after failure of first-line chemotherapy in the NCCN guideline.26 In the context of clinical trials, PD-L1 protein expression on tumour cells detected by immunohistochemistry is currently the best predictive biomarker.[11], [12], [27]
It is conventionally accepted that coagulative necrosis, a common feature of solid tumours, is caused by chronic ischaemic injury, which suggests that the degree of tumour necrosis reflects the level of intratumoural hypoxia. Several recent reports suggested that hypoxia might induce epithelial–mesenchymal transition and cause conformational changes.28
Hypoxia-inducible factor 1-α (HIF-1α) is a major transcription factor that mediates adaptive responses to hypoxia, and the protein consists of HIF-1α and HIF-1β subunits. HIF-1α is the functional subunit, and it is regulated by oxygen levels. Meanwhile, HIF-1β is a constitutively expressed nuclear protein.29
Hypoxia causes a rapid, dramatic, and selective upregulation of PD-L1 on splenic myeloid-derived suppressor cells in tumour-bearing mice. It also significantly increases the expression of PD-L1 on macrophages, dendritic cells, and tumour cells. Furthermore, PD-L1 upregulation under hypoxia is dependent on HIF-1α.30
The goal of this study was to conduct a comprehensive investigation of PD-L1 and HIF-1α expression in a large series of patients with highly aggressive PPC and correlate their expression with clinicopathologic parameters and clinical outcomes, as well as the major driver mutations of NSCLC in East Asians.
Section snippets
Patient populations
The investigations were performed in a cohort of 122 individuals with PPC, including 42 cases from our previous reports,31 who were managed at the National Taiwan University Hospital between 30th January 1996 and 27th July 2015. The Hospital's Research Ethics Committee approved the study, and all patients provided written informed consent. PPCs were diagnosed according to the criteria set by the World Health Organisation.3
Clinical data were tabulated from each patient's medical records and
Patient demographics
Eighty-nine (73%) of the patients were men, and 33 (27%) patients were women (Table 1). Eighty-two (67.2%) patients were smokers. The mean age at diagnosis was 64.0 years (range, 23–93 years). The distribution of stages of PPC among the patients was as follows: stage I disease, 13 patients (10.7%); stage II disease, 15 patients (12.3%); stage III disease, 42 patients (34.4%); and stage IV disease, 52 patients (42.6%) (Table 1). Eighty-eight patients with advanced disease received chemotherapy,
Discussion
PPC is a rare, aggressive disease characterised by a high rate of early distant metastasis, late recognition, and ominous outcomes.[1], [31], [42] The etiologic and molecular events associated with this disease are almost entirely unknown. There are presently no available data indicating the optimal management of patients with advanced PPC.
Considerable evidence indicates that the EGFR pathway plays an important role in the pathogenesis of lung cancers. Patients with EGFR-mutated NSCLC respond
Conflict of interest statement
The authors declare no conflicts of interest.
Role of the funding sources
This study is funded by the National Taiwan University Hospital, Taipei, Taiwan (NTUH 105-S2939) for the conduct of the research and the Ministry of Science and Technology, Taiwan (104-2314-B-002-090) for the English editing and reproduction of colour artwork of this article.
Acknowledgements
The authors would like to thank Ms. Chih-Hsin Chen for her skillful technical support.
References (66)
- et al.
Pulmonary pleomorphic (spindle) cell carcinoma: peculiar clinicopathologic manifestations different from ordinary non-small cell carcinoma
Lung Cancer
(2001) - et al.
Clinical characteristics of pleomorphic carcinoma of the lung
Lung Cancer
(2010) - et al.
Palliative chemotherapy for pulmonary pleomorphic carcinoma
Lung Cancer
(2007) - et al.
Tumor B7-H1 and B7-H3 expression in squamous cell carcinoma of the lung
Clin Lung Cancer
(2013) - et al.
Programmed cell death-ligand 1 expression in surgically resected stage I pulmonary adenocarcinoma and its correlation with driver mutations and clinical outcomes
Eur J Cancer
(2014) - et al.
Programmed death ligand-1 expression in non-small cell lung cancer
Lab Invest
(2014) - et al.
Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its α subunit
J Biol Chem
(1996) - et al.
PD-L1 is highly expressed in lung lymphoepithelioma-like carcinoma: a potential rationale for immunotherapy
Lung Cancer
(2015) - et al.
Associations among pretreatment tumor necrosis and the expression of HIF-1α and PD-L1 in advanced oral squamous cell carcinoma and the prognostic impact thereof
Oral Oncol
(2015) - et al.
Hypoxia-induced up-regulation of angiotenin, besides VEGF, is related to progression of oral cancer
Oral Oncol
(2012)