Clinicopathological analysis of PD-L1 and PD-L2 expression in pulmonary squamous cell carcinoma: Comparison with tumor-infiltrating T cells and the status of oncogenic drivers
Introduction
Non-small cell lung cancer (NSCLC), which accounts for 85% of all lung cancers, is the leading cause of cancer-related death worldwide [1]. Among NSCLCs, adenocarcinoma (ADC) and squamous cell carcinoma (SqCC) are two major histological subtypes that exhibit distinct epidemiologic, biological and genetic characteristics [2]. SqCC frequently occurs in males in the central pulmonary airway, and it is etiologically closely associated with tobacco smoking [3].
In the past decade, the management of NSCLC has evolved from conventional therapy to personalized targeted therapy based on the status of oncogenic drivers in the tumor cells. Particularly, small molecule inhibitors targeting EGFR or ALK prolonged the survival of pulmonary ADC patients carrying an EGFR mutation or an ALK translocation [4], [5], [6]. Moreover, various genetic alterations involving ROS1, RET, BRAF, HER2, and MET have been identified in pulmonary ADC [7]. In contrast, SqCC has been associated with recurrent genetic alterations of FGFR1, PI3K, DDR2, and MET, and these associations have provided the rationale for targeted therapies in pulmonary SqCC (pSqCC) [7], [8], [9]. Recently, immune checkpoint-targeted immunotherapy has demonstrated a favorable clinical outcome in NSCLCs, thereby emerging as an alternative therapeutic strategy [10], [11].
Cancer evades host immune surveillance via the utilization of immune checkpoints [12]. These checkpoints include PD-1/PD-L1 (or PD-L2)-mediated interactions between T cells and antigen-presenting cells (APCs) or host cells. These pathways deliver inhibitory signals to immune cells, thereby contributing to the maintenance of self-tolerance and the regulation of immune responses under physiologic conditions. PD-1, which is expressed on T cells, attenuates immune responses by inhibiting effector T-cell proliferation and function upon its engagement by PD-L1 or PD-L2 [13]. Furthermore, a blockade of PD-1/PD-L1 interactions restores effector T-cell function and enhances anti-tumor immune responses in vivo [14]. Consistently, blocking antibodies against PD-1 and PD-L1 have exerted clear effect with objective response and disease control in NSCLC patients with squamous or non-squamous histology based on phase 1 clinical trials [10], [15], [16]. Thus, PD-1/PD-L1 pathway-targeted immunotherapy has emerged as a highly promising therapeutic strategy for pSqCC. Consistently, several reports have demonstrated variable positive PD-L1 expression in pSqCC [17], [18], [19], [20], [21]. Given that PD-Ls on tumor cells or APCs interact with PD-1 on T cells in the tumor microenvironment, a comprehensive analysis of PD-1/PD-L-related molecules might provide invaluable information for determining the biological and clinical relevance of the PD-1/PD-Ls pathway to pSqCC. Therefore, we investigated the expression patterns of PD-L1 and PD-L2 in tumor cells and the number of PD-1+ and CD8+ tumor-infiltrating lymphocytes (TILs) in a large cohort of pSqCC cases. Moreover, we analyzed the clinicopathological characteristics of PD-L1- and PD-L2-expressing SqCC and the status of the oncogenic drivers including EGFR, FGFR1, and MET. We demonstrated that PD-L1 and PD-L2 expression in pSqCC was closely associated with increased CD8+ TILs and MET expression.
Section snippets
Patients and samples
A total of 331 patients with primary pSqCC who underwent surgical resection at Seoul National University Hospital (SNUH, Seoul, Korea) from 2004 to 2012 were included in this study. None of the patients had received neoadjuvant chemotherapy or radiotherapy or exhibited distant metastasis at the time of diagnosis. Metastatic tumors were found in the regional lymph nodes of 77 of these patients, which were comparatively analyzed with the primary tumors. Tissue microarrays (TMAs; 2 mm diameter)
Clinicopathological and genetic characteristics of the patients
The clinicopathological and genetic characteristics and expression pattern of PD-1-related molecules in the patients with pSqCC are shown in Table 1 and Supplementary Table S1. In brief, most of the patients (95.8%) were male with an age from 37 to 88 years (mean ± SD = 66.35 ± 8.21 years). The majority of patients (90.9%) were smokers, ranging from 1 to 170 pack years (mean ± SD = 46.75 ± 23.82 pack years). An EGFR mutation and positive EGFR FISH were detected in 3.8% and 30.1% of the patients,
Discussion
This study demonstrated that PD-L1 and PD-L2 expression was observed in 26.9% and 23.9% of pSqCC cases, respectively. This PD-L1 expression rate was similar to previously reported rates (from 19.6 to 36.1%) [18], [21], whereas PD-L2 expression had not yet been explored in pSqCC. Regarding PD-L1 in NSCLC, previous studies focused on ADC rather than SqCC and were not subjected to detailed histological analysis [17], [18], [19], [21]. Furthermore, no previous reports have described the correlation
Conflict of interest statement
The authors have declared no conflicts of interest related directly or indirectly to this paper.
Funding
This study was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (1220220).
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These authors contributed equally to this work.