Biochemical and Biophysical Research Communications
Programmed death ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density differences between paired primary and brain metastatic lesions in non-small cell lung cancer
Introduction
Non-small cell lung cancer (NSCLC) accounts for 85–90% of lung cancers, which are the leading cause of cancer-related death globally [1]. One of the most frequent and serious complications of this ubiquitous disease is metastasis to the brain [2,3]. Therapy options for patients with NSCLC and brain metastases (BMs) remain limited and unsatisfactory, and the prognosis is very poor even after positive treatment [4,5]. The new development of antibodies that target programmed cell death-1 (PD-1) or programmed death ligand 1 (PD-L1) represents a vital improvement in metastatic NSCLC therapy, with PD-1 inhibitors demonstrating impressive antitumor activity against BMs in NSCLC patients. Nevertheless, the response rates of primary lung cancer and corresponding metastatic brain lesions are not exactly the same [6,7]. Understanding the potential reasons for this discordance can provide valuable clues as to improve patient selection and treatment outcomes.
PD-L1 (also known as B7-H1), an immune-inhibitory molecule, is known to be expressed on tumor cells (TCs) and tumor-infiltrating immune cells (ICs) that suppresses antitumoral T-cell function through binding to PD-1 and B7.1 receptors on activated T and B cells [8]. Based on the results from clinical trials, PD-L1 expression was identified to be a predictive biomarker of response to PD-1/PD-L1 blockade therapy [[9], [10], [11], [12]]. Interestingly, growing evidence suggests that PD-L1 is a dynamic biomarker subject to changes due to the tumor microenvironment [13,14]. In line with this, a recent report showed that PD-L1 expression can be heterogenic depending on the metastatic sites and histological transformation [15]. In this regard, a comprehensive assessment of PD-L1 expression is important to determine optimal therapeutic strategies. However, studies regarding the inter-tissue heterogeneity of PD-L1 expression in NSCLC BM patients is very limited.
PD-L1 expression in the tumor microenvironment is often associated with tumor-infiltrating lymphocytes (TILs), of which CD8+ TILs may be the most potent. CD8+ TILs can induce or maintain PD-L1 expression by secreting interferon (IFN)-γ [16]; on the other hand, PD-L1 expression also contributes to apoptosis of CD8+ TILs [17]. It is noteworthy that besides PD-L1, pre-existing CD8+ T cells within tumor lesions are also a potential therapeutic response marker of PD-1 pathway inhibitors [13,18]. Moreover, CD8+ TIL density has been reported as a significant prognostic factor alone or in combination with other markers in a spectrum of different tumor types including NSCLC [[19], [20], [21]]. Given the dynamics of PD-L1 expression, we wonder if the CD8+ TIL accumulation in tumors is also dynamic. To date, for NSCLC patients with BMs, whether the CD8+ TIL density between primary tumors and their corresponding BMs is consistent remains less clear.
To address these issues, here, we retrospectively analyzed the prevalence and concordance of the PD-L1 expression between primary lesions and BMs in advanced NSCLC patients. We also compared the CD8+ TIL counts within the cancer parenchyma and stroma between paired tumors and evaluated its prognostic value.
Section snippets
Patients
The study included 25 patients with NSCLC and BMs from three academic medical centers of the Third Military Medical University (Chongqing, China), and was conducted between January 2006 and September 2014. Among the patients, 2 were diagnosed with NSCLC based on the pathological examination of biopsy specimens and underwent a surgical resection of the brain metastatic lesions (alone) to alleviate the symptoms. The remaining 23 patients underwent surgical resection of both the primary lung
Patient demographics and clinicopathologic characteristics
The characteristics of 25 NSCLC BM patients were listed in Table 1. The median age of all patients was 57 years (range: 26–78 years). These patients tended to be male (72%), non-smokers (52%), and the Karnofsky Performance Status (KPS) score of most patients (80%) was not less than 80. All patients harbored brain metastatic lesion. Eleven (44%) of these patients were diagnosed with synchronous BM, and 14 patients (56%) were diagnosed with metachronous BM. Adenocarcinoma (80%) was the major
Discussion
BM are very common in NSCLC patients. At diagnosis, approximately 10% of NSCLC patients have BMs, and another 30% develop BM lesions during the course of their diseases [2]. The recent FDA approval PD-1 inhibitors, pembrolizumab and nivolumab, have shown to be effective and tolerable in NSCLC patients with BMs [6,7]. However, the objective response rates between primary lung cancer and their intracranial lesions are not exactly concordant [7]. Herein, we determined a spatial and temporal
Conflicts of interest
The authors declare no conflicts of interest.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (Grant number: 81472648).
We thank Dr. X.D and J.C (Third Military Medical University) for technical assistance with immunohistochemistry staining; and Editage for English language editing.
B.Z., Z.Y., Q.J. and J.Z. have participated in conception and design; J.Z., Z.G. and Y.W. performed experiments, collected data; J.Z. and Z.G. contributed to data analysis and interpretation; J.Z. wrote the manuscript; All authors have
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These authors contributed equally to this work.