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SHORT COMMUNICATION
Year : 2020  |  Volume : 65  |  Issue : 6  |  Page : 506-509
Expression of programmed death-ligand 1 in cutaneous squamous cell carcinoma arising in sun-exposed and nonsun-exposed skin


Department of Medicine of Sensory and Motor Organs, Division of Dermatology, Faculty of Medicine, Tottori University, Tottori, Japan

Date of Web Publication23-Oct-2020

Correspondence Address:
Hiroyuki Goto
Department of Medicine of Sensory and Motor Organs, Division of Dermatology, Faculty of Medicine, Tottori University, 36-1, Nishicho, Yonago, Tottori 683-8504
Japan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijd.IJD_187_19

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   Abstract 


Background: A recent clinical trial has shown the efficacy of an anti-programmed death-1 (PD-1) antibody against advanced squamous cell carcinoma (SCC). The expression of PD-ligand 1 (PD-L1) in tumor cells correlates with a favorable response to anti-PD-1 therapy in various malignancies. In recent studies, it has been shown that SCC frequently expresses PD-L1. However, there has been no previous study focusing on the difference in PD-L1 expression between SCC in sun-exposed skin and that in nonsun-exposed areas. Aims: The purpose of this study was to investigate the relationship between sun-exposure status and PD-L1 expression in patients with SCC. Materials and Methods: We investigated 80 patients with SCC (40 patients with SCC in sun-exposed skin and 40 patients with SCC in nonsun-exposed skin) by immunohistochemical staining for PD-L1. Fisher's exact test was used for statistical analyses of the differences between the two groups. Results: Patients with SCC in sun-exposed skin showed a significantly higher expression level of PD-L1 in tumor cells than did patients with SCC in nonsun-exposed skin (P = 0.0133). Conclusions: We found that the expression level of PD-L1 in patients with SCC in sun-exposed skin was higher than in patients with SCC in nonsun-exposed skin. Practical data are needed for appropriate applications of new therapeutic options for SCC.


Keywords: Immune checkpoint inhibitor, programmed death-1, programmed death-ligand 1, squamous cell carcinoma


How to cite this article:
Goto H, Sugita K, Yamamoto O. Expression of programmed death-ligand 1 in cutaneous squamous cell carcinoma arising in sun-exposed and nonsun-exposed skin. Indian J Dermatol 2020;65:506-9

How to cite this URL:
Goto H, Sugita K, Yamamoto O. Expression of programmed death-ligand 1 in cutaneous squamous cell carcinoma arising in sun-exposed and nonsun-exposed skin. Indian J Dermatol [serial online] 2020 [cited 2020 Nov 29];65:506-9. Available from: https://www.e-ijd.org/text.asp?2020/65/6/506/298902





   Introduction Top


Cutaneous squamous cell carcinoma (SCC) is a relatively common nonmelanoma skin cancer that develops in association with ultraviolet (UV) ray exposure, irradiation, scar tissue after a trauma or burn, Bowen's disease, or a chronic wound such as osteomyelitis or decubitus ulcer.[1] Cases of SCC have recently been increasing due to increase in the frequency of UV ray exposure, ozone depletion, and increase in longevity.[2] Although the mortality rate from SCC is quite low, some patients with SCC have metastatic lesions, and effective chemotherapy with valid evidence has not been established for such patients.[2],[3] Recently, treatment with an anti-programmed death-1 (PD-1) antibody has resulted in a dramatic improvement in the prognosis of several malignancies, including melanoma and lung cancer, and the results of a clinical trial for unresected SCC have recently been reported.[3],[4],[5] Recent studies have suggested that the expression of programmed death-ligand 1 (PD-L1) in tumor cells might correlate with a favorable response to anti-PD-1 therapy.[6] Some studies have shown that SCC often express PD-L1.[7],[8],[9],[10],[11],[12],[13]

Although chronic sun exposure is the primary cause of most cases of SCC, it may also occur as a complication of burn scars where skin is not damaged by UV light exposure.[14] Bowen's disease can also occur on nonsun-exposed skin. This evidence prompted us to investigate whether PD-L1 expression is associated with sun exposure. However, the influence of sun exposure on PD-L1 in SCC has not been discussed in detail. In this study, we evaluated the difference between expression of PD-L1 in SCC over sun-exposed and nonsun-exposed skin.


   Materials and Methods Top


Patients

Eighty patients (40 patients with SCC in sun-exposed skin and 40 patients with SCC in nonsun-exposed skin) who were diagnosed as having SCC and who received surgical treatment in Tottori University were included in this study. This study was carried out in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Tottori University, Faculty of Medicine, Japan (No. 17A076). Informed consent was obtained from each patient enrolled in this study.

Immunohistochemistry

Formalin-fixed and paraffin-embedded 4-μm-thick sections of specimens were used for immunohistochemistry. Immunohistochemical staining for PD-L1 in tumor cells was performed as reported previously using Roche Biomedical Ventana antibodies (PD-L1; SP263).[11] PD-L1 assays were performed according to the manufacturer's specifications using the Ventana Ultraview System (Roche Diagnostics, Basel, Switzerland). The percentage of PD-L1-positive cells was calculated by light microscopy. At first, we randomly chose three areas in each lesion and counted the number of tumor cells in those three areas. Next, we counted the number of tumor cells expressing PD-L1 in those three areas. Finally, we calculated the percentage of tumor cells expressing PD-L1. Necrotic, keratinized, and inflammatory cells were excluded. Membrane staining of tumor cells was defined as positive, and cytoplasmic staining of tumor cells was excluded. Normal lymph nodes were stained with PD-L1 antibodies as a positive control [Figure 1]a and [Figure 1]b. PD-L1 was not expressed on normal skin in both sun-exposed and nonsun-exposed areas. We defined a specimen containing at least 1% of tumor cell-expressing PD-L1 as a positive case and a specimen containing <1% of tumor cell-expressing PD-L1 as a negative case, as previously reported.[8],[12]
Figure 1: (a and b) H and E, and Positive control for programmed death ligand 1 staining of normal lymph node with IHC showing positive lymphocytes staining brown (×40); (c and d) tumor cells of squamous cell carcinoma in sun exposed skin (H and E, ×40) and high concentration of PD-L1 positive cells (IHC, ×40); (e and f) tumor cells of squamous cell carcinoma in non-sun exposed skin (H and E, ×100) with less than normal PD-L1 positive cells (IHC, ×100). IHC-Immunohistochemistry

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Statistical analysis

Fisher's exact test was used for statistical analysis of differences between the two groups. A P <0.05 was considered statistically significant. Statistical analyses were performed using GraphPad Prism 7 software (GraphPad Software, La Jolla, CA, USA).


   Results Top


Patients' background

Patients' data are presented in [Table 1]. The face was the most frequent site in the group of SCC in sun-exposed skin and the leg was the most frequent site in the group of SCC in nonsun-exposed skin.
Table 1: Clinical summary of patients enrolled in this study

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Expression of programmed death-ligand 1 in tumor cells

The results of analysis of PD-L1 expression are shown in [Table 2]. Twenty-seven patients (67.5%) in the group of SCC in sun-exposed skin had 1% or more of tumor cell-expressing PD-L1 and 15 patients (37.5%) in the group of SCC in nonsun-exposed skin had 1% or more of tumor cell-expressing PD-L1 (P = 0.0133) [Figure 1]c, [Figure 1]d, [Figure 1]e, [Figure 1]f.
Table 2: Results of analysis of programmed death-ligand 1 expression

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   Discussion Top


In reported studies, 20%–70% of the patients with SCC had PD-L1 expression in tumor cells.[7],[8],[9],[10],[11],[12],[13] In the present study, 52.5% of the patients had PD-L1 expression in tumor cells. Although the expression of PD-L1 in sun-exposed skin and that in nonsun-exposed skin were evaluated in some previous studies, no statistically significant difference was found.[12],[13] However, the number of patients with SCC in nonsun-exposed skin in those studies was relatively small.[12],[13] In our study, a significant correlation was found between sun exposure and expression of PD-L1 in tumor cells. According to a previous study, SCC has a high mutation burden because of the damage caused by UV light.[15] In patients with Merkel cell carcinoma, another type of nonmelanoma skin cancer, Wong et al.

reported that Merkel cell polyoma virus-negative Merkel cell carcinoma was associated with UV-induced DNA damage and that UV-induced DNA damage caused a high mutation burden and high expression level of PD-L1 in tumor cells.[16] Therefore, in patients with SCC, the reason for the expression level of PD-L1 in sun-exposed skin being higher than that in nonsun-exposed skin may be the mutation burden due to sun exposure. SCC has various precursor lesions (Bowen's disease, actinic keratosis, scar tissue, and chronic wound). The precursor lesion may affect the expression of PD-L1, and further research is needed.

A recent clinical trial has shown that cemiplimab, a new agent of an anti-PD-1 antibody, induced a response in about half of the patients with advanced SCC.[3] In that trial, although the expression of PD-L1 in tumor cells was not evaluated, it may be possible to use expression of PD-L1 for prediction of the response to treatment. Another study showed that expression of PD-L1 in other tumors, such as malignant melanoma, correlated with the efficacy of anti-PD-L1 treatment.[17] Thus, differential expression of PD-L1 between sun-exposed SCC and nonsun-exposed SCC would impact on immune responses during anti-PD-L1 treatment, potentially resulting in the differential therapeutic responses to PD-L1 blockade. In the present study, we showed that the expression level of PD-L1 in patients with SCC in sun-exposed skin is significantly higher than that in patients with SCC in nonsun-exposed skin. Practical data are needed for appropriate applications of new therapeutic options for SCC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Goto H, Yoshikawa S, Nakagawa M, Murata H, Wasa J, Omodaka T, et al. Two cases of squamous cell carcinoma of the lower leg treated with a pasteurized bone graft. Eur J Dermatol 2016;26:322-4.  Back to cited text no. 1
    
2.
Leiter U, Eigentler T, Garbe C. Epidemiology of skin cancer. Adv Exp Med Biol 2014;810:120-40.  Back to cited text no. 2
    
3.
Migden MR, Rischin D, Schmults CD, Guminski A, Hauschild A, Lewis KD, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med 2018;379:341-51.  Back to cited text no. 3
    
4.
Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015;16:375-84.  Back to cited text no. 4
    
5.
Gettinger S, Rizvi NA, Chow LQ, Borghaei H, Brahmer J, Ready N, et al. Nivolumab monotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 2016;34:2980-7.  Back to cited text no. 5
    
6.
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369:122-33.  Back to cited text no. 6
    
7.
Slater NA, Googe PB. PD-L1 expression in cutaneous squamous cell carcinoma correlates with risk of metastasis. J Cutan Pathol 2016;43:663-70.  Back to cited text no. 7
    
8.
Gambichler T, Gnielka M, Rüddel I, Stockfleth E, Stücker M, Schmitz L, et al. Expression of PD-L1 in keratoacanthoma and different stages of progression in cutaneous squamous cell carcinoma. Cancer Immunol Immunother 2017;66:1199-204.  Back to cited text no. 8
    
9.
Jiao Q, Liu C, Li W, Li W, Fang F, Qian Q, et al. Programmed death-1 ligands 1 and 2 expression in cutaneous squamous cell carcinoma and their relationship with tumour- infiltrating dendritic cells. Clin Exp Immunol 2017;188:420-9.  Back to cited text no. 9
    
10.
García-Pedrero JM, Martínez-Camblor P, Diaz-Coto S, Munguia-Calzada P, Vallina-Alvarez A, Vazquez-Lopez F, et al. Tumor programmed cell death ligand 1 expression correlates with nodal metastasis in patients with cutaneous squamous cell carcinoma of the head and neck. J Am Acad Dermatol 2017;77:527-33.  Back to cited text no. 10
    
11.
Roper E, Lum T, Palme CE, Ashford B, Ch'ng S, Ranson M, et al. PD-L1 expression predicts longer disease free survival in high risk head and neck cutaneous squamous cell carcinoma. Pathology 2017;49:499-505.  Back to cited text no. 11
    
12.
Schaper K, Köther B, Hesse K, Satzger I, Gutzmer R. The pattern and clinicopathological correlates of programmed death-ligand 1 expression in cutaneous squamous cell carcinoma. Br J Dermatol 2017;176:1354-6.  Back to cited text no. 12
    
13.
Kamiya S, Kato J, Kamiya T, Yamashita T, Sumikawa Y, Hida T, et al. Association between PD-L1 expression and lymph node metastasis in cutaneous squamous cell carcinoma. Asia Pac J Clin Oncol 2018. doi: 10.1111/ajco.13102. [Epub ahead of print].  Back to cited text no. 13
    
14.
Rowe DE, Carroll RJ, Day CL Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol 1992;26:976-90.  Back to cited text no. 14
    
15.
Pickering CR, Zhou JH, Lee JJ, Drummond JA, Peng SA, Saade RE, et al. Mutational landscape of aggressive cutaneous squamous cell carcinoma. Clin Cancer Res 2014;20:6582-92.  Back to cited text no. 15
    
16.
Wong SQ, Waldeck K, Vergara IA, Schröder J, Madore J, Wilmott JS, et al . UV-associated mutations underlie the etiology of MCV-negative merkel cell carcinomas. Cancer Res 2015;75:5228-34.  Back to cited text no. 16
    
17.
Lin H, Wei S, Hurt EM, Green MD, Zhao L, Vatan L, et al. Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression. J Clin Invest 2018;128:805-15.  Back to cited text no. 17
    


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    Tables

  [Table 1], [Table 2]



 

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