CD274/PD-L1 gene amplification and PD-L1 protein expression are common events in squamous cell carcinoma of the oral cavity - PubMed (original) (raw)

CD274/PD-L1 gene amplification and PD-L1 protein expression are common events in squamous cell carcinoma of the oral cavity

Melanie Straub et al. Oncotarget. 2016.

Abstract

Immunomodulatory therapies, targeting the immune checkpoint receptor-ligand complex PD-1/PD-L1 have shown promising results in early phase clinical trials in solid malignancies, including carcinomas of the head and neck. In this context, PD-L1 protein expression has been proposed as a potentially valuable predictive marker. In the present study, expression of PD-L1 and PD-1 was evaluated by immunohistochemistry in 80 patients with predominantly HPV-negative oral squamous cell carcinomas and associated nodal metastasis. In addition, CD274/PD-L1 gene copy number status was assessed by fluorescence in situ hybridization analysis. PD-L1 expression was detected in 36/80 (45%) cases and concordance of PD-L1 expression in primary tumor and corresponding nodal metastasis was present in only 20/28 (72%) cases. PD-1 expression was found in tumor-infiltrating lymphocytes (TILs) but not in tumor cells. CD274/PD-L1 gene amplification was detected in 19% of cases, with high level PD-L1 amplification present in 12/80 (15%), and low level amplification in 3/80 (4%). Interestingly, CD274/PD-L1 gene amplification was associated with positive PD-L1 immunostaining in only 73% of cases. PD-L1 copy number status was concordant in primary tumor and associated metastases. Clinically, PD-L1 tumor immunopositivity was associated with a higher risk for nodal metastasis at diagnosis, overall tumor related death und recurrence. Based on our findings we propose to include PD-L1 copy number status in addition to protein status in screening programs for future clinical trials with immunotherapeutic strategies targeting the PD-1/PD-L1 axis.

Keywords: PD-1; PD-L1; Pathology Section; fluorescence in situ hybridization; gene amplification; oral squamous cell carcinoma.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1. Squamous cell carcinoma of the head and neck, showing membraneous PD-L1 expression in tumor cells with

a. strong staining (3+), b. intermediate staining (2+) and c. weak staining (1+) intensity. Fibroblasts within tumor stroma are negative. d) PD-1 staining in squamous cell carcinoma with intermingled tumor-infiltrating lymphocytes (TILs). PD-1 staining is only seen in TILs, while carcinoma cells are negative. (a.-c. PD-L1 immunohistochemistry, d. PD-1 immunohistochemistry).

Figure 2

Figure 2. Concordance and discordance of PD-L1 expression in primary tumor and matched lymph node metastases

Figure 3

Figure 3. Fluorescence _in situ_-hybridization (FISH) for PD-L1

PD-L1 gene is labelled in green, centromer 9 in red. FISH analysis showing a., b. high level amplification, with PD-L1/CEP9 ratio ≥ 4, indicated by clusters of green fluorochrome labeling PD-L1 c. low level amplification, PD-L1/CEP9 ratio ≥ 2.0 - < 4; d. Polysomy of PD-L1 gene locus; e. PD-L1 disomy. (a.-d. SPEC _CD274, PDCD1LG2/CEN_9 Dual Color Probe).

Figure 4

Figure 4. Overall tumor-related survival and recurrence-free survival in patients with SCC of the oral cavity with respect to PD-L1 immunohistochemical status

Overall tumor-related survival a. and recurrence-free survival b. is worse in SCC patients with tumoral PD-L1 immunopositivity (p = 0.01 and 0.05, respectively).

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