Programmed cell death-ligand 1 expression in surgically resected stage I pulmonary adenocarcinoma and its correlation with driver mutations and clinical outcomes

Abstract

Background

Programmed cell death-ligand 1 (PD-L1) is expressed in a group of cancers that may be suitable targets for specific immunotherapy. This study investigated the expression of PD-L1 in surgically resected stage I adenocarcinomas and correlated this with known major driver mutations and clinical outcomes.

Materials and methods

One hundred and sixty-three patients with surgically resected stage I adenocarcinomas were explored. Paraffin-embedded tumour sections were stained with PD-L1 antibody. Tumours with moderate-to-strong membrane staining in ⩾5% of tumour cells were scored as positive for PD-L1 overexpression. The driver mutation epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), and v-raf murine sarcoma viral oncogene homolog B (BRAF) were examined by direct sequencing and anaplastic lymphoma kinsase (ALK) by immunohistochemistry. The correlations of PD-L1 expression with major driver mutations and clinicopathologic parameters were analysed.

Results

The overall frequency of PD-L1 overexpression was 39.9% (65/163). PD-L1 had higher positive results in tumours with higher grade differentiation and vascular invasion and PD-L1 expression was not associated with the expressions of EGFR, KRAS, BRAF and ALK. Multivariate analysis revealed that abnormal carcinoembryonic antigen (CEA) and higher grade of differentiation were risk factors for poor relapse-free survival (RFS) and PD-L1 expression correlated with better RFS. Advanced pathologic stage was the independent risk for poor overall survival (OS).

Conclusions

The PD-L1 expression can be used as a prognostic indicator predictive of RFS in patients with surgically resected stage I lung adenocarcinomas. There may be a possibility for immunotherapy targeting the PD-L1 pathway in patients with lung adenocarcinoma in the future.

Introduction

Lung cancer, especially non-small cell lung cancer (NSCLC), is currently the leading cause of cancer-related death in the United States and worldwide [1]. Most lung cancer patients are diagnosed at an advanced stage, while conventional platinum-based chemotherapy has improved survival within its greatest effectiveness [2]. In the past decades, molecular targeted therapy for the predominant cell type, lung adenocarcinoma, has been the major breakthrough in lung cancer treatment [3]. With the understanding of cancer biology and oncogenic mutations, patients harbouring specific mutations may have significant and durable responses from targeted therapies [4]. However, cancer cells are highly adaptable and may acquire additional mutations and evolve to become drug-resistant, resulting in disease progression clinically [5].

Immunotherapy has been studied to redirect host immune responses to match the adaptability of cancer cells. In terms of NSCLC, allogenic cancer vaccines, autologous cell therapy and T-cell modulating agents are the most studied immunotherapies currently [6], while multiple agents are being investigated in phase II or III trials [7]. T-cells are dominant in host antitumour immune function by their capability of recognising cancer cells as abnormal and by further generating a population of cytotoxic T lymphocytes that can infiltrate the tumour mass and kill tumour cells. The checkpoints of T-cell activation refer to the inhibitory pathway that is crucial for maintaining self-tolerance and avoiding physiologic immune response-related bystander tissue damage [8]. Cancer cells can evade host immune systems by expressing certain ligands to down-regulate cytotoxic T lymphocytes through these inhibitory pathways, which are usually initiated by ligand-receptor interactions. Thus, blocking the specific ligand or receptor by antibodies may lead to the reactivation of host immune responses and antitumour effects [8].

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) acts as an inhibitory receptor for down-regulating T-cell activation at its initial stage, and is also the first corroborated target of checkpoint blockade in cancer therapy. Ipilimumab, an anti-CTLA-4 monoclonal antibody, has a promising effect on improving overall survival of patients with previously treated metastatic melanoma [9] and has been investigated in a phase II trial for treatment of NSCLC, with promising results [10]. However, this therapy is frequently accompanied by severe and unfavourable immune reactions. Programmed cell death-1 (PD-1) is another immune checkpoint expressed on the surface of T-cells upon activation [11]. Programmed cell death-ligand 1 (PD-L1) (B7-H1) is the major ligand for PD-1 and is expressed in various type of cancers [12]. Both anti-PD-1 [13] and anti-PD-L1 [14] monoclonal antibodies have been studied in phase I clinical trials. Some patients with NSCLC have had durable and significant responses. Tumour expression of PD-L1, which is detected by immunohistochemistry in formalin-fixed paraffin-embedded tissue samples, has been associated with positive responses to anti-PD-1 or anti-PD-L1 treatment [13], [14], [15]. However, data regarding the prevalence and prognostic role of PD-L1 expression in NSCLC are limited and the results of several small series studies are inconsistent [16], [17], [18], [19].

This study focused on patients with resected stage I pulmonary adenocarcinoma and evaluated the association of PD-L1 expression with clinicopathologic parameters and clinical outcomes, as well as the major driver mutations of lung adenocarcinoma in East Asians, including mutations in the genes of epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog B (BRAF) and anaplastic lymphoma kinase (ALK).