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

https://doi.org/10.1016/j.bbrc.2018.03.053Get rights and content

Highlights

  • The prevalence of PD-L1 expression on tumor cells and tumor-infiltrating immune cells was discrepant in NSCLC BM patients.

  • PD-L1 expression had a spatial and temporal discrepancy in NSCLC patients with brain metastasis.

  • For NSCLC BM patients, CD8+ tumor-infiltrating lymphocyte density showed a spatial and temporal heterogeneity.

  • Stromal CD8+ cell numbers in the brain metastatic lesions may be a potential prognostic factor for NSCLC BM patients.

Abstract

Immunotherapy targeting the programmed cell death-1/programmed death ligand 1(PD-L1) pathway has shown promising antitumor activity in brain metastases (BMs) of non-small cell lung cancer (NSCLC) patients with an acceptable safety profile; however, the response rates often differ between primary lesions and intracranial lesions. Studies are necessary to identify detailed characterizations of the response biomarkers. In this study, we aimed to compare the differences of PD-L1 expression and CD8+ tumor-infiltrating lymphocyte (TIL) density, two major response biomarkers of PD-1/PD-L1 blockade, between paired primary and brain metastatic lesions in advanced NSCLC. We observed that among primary lesions or BMs, only a small number of patients harbored common PD-L1 expression on both tumor cells and tumor-infiltrating immune cells. Additionally, we found that the numbers of CD8+ TILs were significantly fewer in BMs than in primary lung cancers. Low stromal CD8+ TIL numbers in BMs were associated with significantly shorter overall survival compared to high stromal CD8+ TIL counts. Notably, we demonstrated a discrepancy in PD-L1 expression and CD8+ TIL density between primary lung cancers and their corresponding BMs. Such heterogeneities are significantly associated with the time at which BMs occurred. Our study emphasizes the spatial and temporal heterogeneity of biomarkers for anti-PD-1/PD-L1 therapy, which should be concerned in clinical practice.

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

References (30)

  • M.V. Dieci et al.

    Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study

    Ann. Oncol.

    (2015)
  • A.S. Mansfield et al.

    Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer

    Ann. Oncol.

    (2016)
  • R.L. Siegel et al.

    Cancer statistics, 2018, CA cancer

    J. Clin

    (2018)
  • T.K. Owonikoko et al.

    Current approaches to the treatment of metastatic brain tumours

    Nat. Rev. Clin. Oncol.

    (2014)
  • R.S. Herbst et al.

    Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients

    Nature

    (2014)
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