Diffuse High Intensity PD–L1 Staining in Thymic Epithelial Tumors

Abstract

Introduction Blockade of the immune checkpoint programmed death receptor ligand-1 (PD-L1)/PD-1 pathway has well-established clinical activity across many tumor types. PD-L1 protein expression by immunohistochemistry (IHC) is emerging as a predictive biomarker of response to these therapies. Here, we examine PD-L1 expression in a thymic epithelial tumor (TET) tissue microarray (TMA). Methods The TMA contained 69 TETs and 17 thymic controls, with each case represented by triplicate cores. The TMA was stained with rabbit monoclonal antibody (clone 15, Sino Biological) to human PD-L1. PD-L1 staining was scored based on intensity as follows: 0=none, 1=equivocal/uninterpretable, 2=weak, and 3=intermediate-strong. Those cases with all cores scoring 3 in the epithelial component were categorized as PD-L1high and the remaining as PD-L1low. Results PD-L1high scores were more frequent in TETs than controls (68.1% vs. 17.6%, p=0.0036). PD-L1 scores and histology were significantly correlated, with higher intensity staining in WHO B2/B3/C TETs. Only 14.8% of TETs had PD-L1 staining of associated lymphocytes. In an adjusted analysis (age/gender), PD-L1high TETs had a significantly worse overall survival (HR 5.40, 95% CI 1.13-25.89, p=0.035) and a trend for worse event-free survival (HR 2.94, 95% CI 0.94-9.24, p=0.064). Conclusions PD-L1 expression was present in all cases of TETs within the epithelial component but only in a minority in the lymphocytic component. TETs stained more intensely for PD-L1 than controls, and PD-L1high TETs were associated with more aggressive histology and worse prognosis. This study lends rationale to a clinical trial with anti-PD1/PD-L1 therapy in this rare tumor type.

Prognostic Value of Programmed Death Ligand 1 and Programmed Death 1 Expression in Thymic Carcinoma

“…In the current study, the PD-L1 clone EPR1161 [2], which recognizes the C-terminus extracellular domains of PD-L1, was employed. In contrast, previous reports studying PD-L1 in thymic epithelial tumors used clone 5H1, which targets extracellular domains of PD-L1, or E1L3N, which targets intracellular domains, respectively (22,23). These three studies (including ours) demonstrated slightly different populations of cases with high PD-L1 expression in thymic carcinoma (58.7%-80%), which may have resulted from the use of distinct antibodies and PD-L1 cut-off values.…”

“…Thus far, few studies have examined PD-L1 expression in thymic epithelial tumors (22)(23)(24). Confined to thymic carcinoma as a subset of thymic epithelial tumors, only one of these reports mentioned the prognostic role of PD-L1, finding that there was no difference in OS according to PD-L1 positivity (23).…”

“…Indeed, PD-L1 expression and PD-1 þ tumor-infiltrating lymphocyte (TIL) abundance have been reported to be prognostic factors in various malignancies (15)(16)(17)(18)(19)(20)(21). In previous reports on PD-L1 expression in thymic epithelial tumors, it was stated that high PD-L1 expression was associated with an advanced Masaoka-Koga stage and more aggressive histologies such as type B2/B3 thymoma or thymic carcinoma (22)(23)(24). In contrast, survival analyses based on PD-L1 expression were inconsistent, as one study determined a significant association between high PD-L1 expression and poor OS in an age-and sex-adjusted analysis, whereas the others did not find any prognostic impact.…”

Moving Immune Checkpoint Blockade in Thoracic Tumors beyond NSCLC

“…129 More recently, PD-L1 positivity has been detected in normal thymus tyissue, thymomas and thymic carcinomas, with an apparent differential distribution between histological grades. 130 131 whilst in the other study PD-L1 high expression was associated with worse OS. 130 Remarkably, in this same study PD-L1 high-expression lymphocytes were detected in 14.8% of TETs (8 of 54) and 29.4% of control samples (5 of 17), but no lymphocyte staining was observed in the other study.…”

Pretreatment biopsy for thymic epithelial tumors—does histology subtype matter for treatment strategy?

“…However, when data becomes available from ongoing systematic genomic analyses of TETs (i.e., The Cancer Genome Atlas), targeted therapies could be a more effective induction therapy in the right subset of TETs, although the 70-80% response rate achieved with chemotherapy will be difficult to surpass. In addition, with the recent detection of programmed-death receptorligand-1 in TETs (44), there may be a role for immunebased therapies, though development of this approach must be made with extreme caution given the high rates of autoimmune disease in patients with thymoma. We see the most important role for histological biopsies in advanced TETs for the exclusion of other malignancies rather than the identification of TET WHO subtype.…”