Elsevier

European Journal of Cancer

Volume 55, March 2016, Pages 7-14
European Journal of Cancer

Original Research
Predictive relevance of PD-L1 expression combined with CD8+ TIL density in stage III non-small cell lung cancer patients receiving concurrent chemoradiotherapy

https://doi.org/10.1016/j.ejca.2015.11.020Get rights and content

Highlights

  • There was a trend for poor survival in stage III non-small cell lung cancer who expressed programmed cell death-ligand 1 (PD-L1).

  • A combination of lack of PD-L1 expression and CD8+ tumour-infiltrating lymphocyte (TIL) density tended to predict favourable survival.

  • PD-L1 in combination with CD8+ TIL could be a useful predictive biomarker.

Abstract

Background

Expression of programmed cell death-ligand 1 (PD-L1) is known to be a mechanism whereby cancer can escape immune surveillance, but little is known about factors predictive of efficacy in patients with locally advanced non-small cell lung cancer (NSCLC). We investigated the predictive relevance of PD-L1 expression and CD8+ tumour-infiltrating lymphocytes (TILs) density in patients with locally advanced NSCLC receiving concurrent chemoradiotherapy (CCRT).

Methods

We retrospectively reviewed 74 consecutive patients with stage III NSCLC who had received CCRT. PD-L1 expression and CD8+ TIL density were evaluated by immunohistochemical analysis.

Results

Univariate and multivariate analyses demonstrated that CD8+ TIL density was an independent and significant predictive factor for progression-free survival (PFS) and OS, whereas PD-L1 expression was not correlated with PFS and OS. Sub-analysis revealed that the PD-L1+/CD8 low group had the shortest PFS (8.6 months, p = 0.02) and OS (13.9 months, p = 0.11), and that the PD-L1-/CD8 high group had the longest prognosis (median PFS and OS were not reached) by Kaplan-Meier curves of the four sub-groups.

Conclusions

Among stage III NSCLC patients who received CCRT, there was a trend for poor survival in those who expressed PD-L1. Our analysis indicated that a combination of lack of PD-L1 expression and CD8+ TIL density was significantly associated with favourable survival in these patients. It is proposed that PD-L1 expression in combination with CD8+ TIL density could be a useful predictive biomarker in patients with stage III NSCLC.

Introduction

Lung cancer is the leading cause of cancer death worldwide [1]. Non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancer cases, and approximately 30% of NSCLC patients present with stage III disease [2]. Concurrent chemoradiotherapy (CCRT) is the standard of care for these patients [3]. Despite intensive research into the treatment of NSCLC, the prognosis of patients with stage III disease remains poor, with a median survival time of approximately 20 months [4], [5], [6].

Programmed death 1 (PD1), which belongs to the CD28 family of proteins, is a receptor expressed on the surface of T cells that regulates their activation and proliferation. Its ligand, programmed death-ligand 1 (PD-L1), is frequently overexpressed in many types of human cancer [7]. The binding of PD-L1 to PD1 induces apoptosis or exhaustion in activated T cells, and blockade of this interaction has been shown to enhance the antitumour activity of T cells [7]. Antibody blockade of PD-1 with its ligand (PD-L1 and PD-L2) has shown promising efficacy against various malignancies, including NSCLC [8], [9], [10]. Preliminary observations of patients with recurrent cancers indicate that clinical responses to immune checkpoint blockers are associated with elevated tumour levels of immune inhibitory signals, such as PD-L1, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and with increased numbers of tumour-infiltrating lymphocyte (TIL) [7], [11], [12], [13], [14], [15]. However, data on the prevalence and prognostic value of PD-L1 expression in NSCLC are limited, and the results of several studies involving small series have been inconsistent [16], [17], [18], [19], [20], [21], [22]. In addition, the clinical relevance of PD-L1 expression in stage III NSCLC patients who have received CCRT has remained unclear. In the present study, therefore, we examined PD-L1 expression and CD8+ TIL density in such patients and investigated their associated clinicopathologic characteristics, prognosis and predictive relevance.

Section snippets

Patients

We retrospectively screened consecutive patients who had been diagnosed as having stage III NSCLC at Kurume University Hospital and Yame General Hospital between 1999 and 2013. Patients who had been diagnosed pathologically as having NSCLC, who had received CCRT with combined platinum-containing chemotherapy, and for whom adequate histological specimens containing abundant tumour cells had been available were eligible for inclusion. The present study was conducted in accordance with the

Patient characteristics

The clinical characteristics of the 74 patients are shown in Table 1. The median age of the patients at diagnosis was 67 years (range, 43–81 years). Sixty-four (86%) of the patients were male, and 53 (72%) patients had a good performance status (PS) (0–1). The most predominant histological type was squamous cell carcinoma (40 patients), followed by adenocarcinoma (34 patients). Forty patients (54%) had stage IIIA disease and 34 (46%) had stage IIIB disease at the time of diagnosis. All patients

Discussion

Although blockade of the PD-1/PD-L1 pathway with monoclonal antibodies has recently emerged as a new therapeutic modality for NSCLC, the association between PD-L1 expression and prognosis in patients with stage III NSCLC has remained largely unknown. In the present study, we examined PD-L1 expression using IHC in stage III NSCLC patients who had received CCRT, and found that patients who showed positive expression of PD-L1 tended to show a poorer survival outcome than patients who were negative

Conflict of interest statement

The authors have no conflicts of interest to declare.

Acknowledgement

There was no funding source to acknowledge for this study.

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