Expression of PD-1 and PD-L1 in Extramammary Paget Disease: Implications for Immune-Targeted Therapy

Abstract

Extramammary Paget disease (EMPD) is a locally aggressive cutaneous malignancy that usually arises in anogenital or axillary skin. Immune checkpoint inhibitors targeting programmed cell death receptor (PD-1) and/or its ligand (PD-L1) are approved for the treatment of several types of cancer, and response to these generally correlates with increased PD-L1 expression by tumor cells. The expression of PD-L1 and composition and density of the tumor-associated immune infiltrate in EMPD have been little studied. To determine whether EMPD might be amenable to immune checkpoint blockade, we analyzed the expression of PD-1 and PD-L1 and the composition and density of the tumor-associated immune infiltrate in EMPD and evaluated associations between biomarker expression and clinicopathologic parameters. Twenty-one EMPD tumors were evaluated for tumor cell PD-L1 expression and for relative expression and distribution of CD3, CD8, PD-1, and PD-L1 in the tumor-associated immune infiltrate by using a combination of visual and image analysis (Aperio ImageScope). In addition, PD-L1 expression was assessed in 10 cases of mammary Paget disease (MPD). In EMPD cases, PD-L1 was expressed by tumor cells (3/21; 14%) and the tumor-associated immune infiltrate (15/21; 71%), and PD-1 was expressed by the tumor-associated immune infiltrate in all cases analyzed (18/18). However, PD-L1 expression by EMPD tumor cells did not correlate with the density of CD3-, CD8-, or PD-1-positive cells in the tumor-associated immune infiltrate or other clinicopathologic parameters. Furthermore, the density of CD3, CD8, PD-1, and PD-L1 in the tumor-associated immune infiltrate did not correlate with any clinicopathologic parameters evaluated with the exception that CD3 positive values were significantly higher in patients who were still alive (median, 1310 cells/mm2; range, 543–2115;) than in those who died (median, 611 cells/mm2; range, 481–908; p = 0.049). In all MPD cases, PD-L1 was absent in tumor cells but present in the tumor-associated immune infiltrate, and PD-L1 expression in lymphocytes was lower in patients with HER2/neu-positive than in those with HER2/neu-negative disease (p = 0.07). Our findings raise the possibility of therapeutic targeting of the PD-1/PD-L1 axis in EMPD.

Comparison of the biomarkers for targeted therapies in primary extra‐mammary and mammary Paget's disease

“…In addition, PD-L1 expression in ICs was significantly lower in patients with HER2-positive compared with HER2-negative EMPD cancers. 35 Duverger et al reported positive expression of PD-L1 on cancer cells in n = 4/7 invasive EMPD, 36 while Karpathiou et al reported that EMPD are characterized by the intense lymphocytic response but without PD-L1 expression on either cancer or immune cells. 37 A single patient in our cohort was included in a basket trial with Pembrolizumab without clinical benefit and a later tumor sample analysis revealed no PD-L1 positivity, but HER2 amplification was detected and Herceptin therapy was initiated (data not shown).…”

PD-1 Signaling in Extramammary Paget Disease

“…infiltrate. 5 They found that PD-1 was expressed heavily by the tumor-associated immune infiltrate in all EMPD cases analyzed. Similar to the previously mentioned study, 6 PD-L1 was expressed by tumor cells in a few cases only.…”

“…Current data for targeted therapy have focused on HER2 (human epidermal growth factor receptor 2) hormone receptor expression, 18 ERBB (erythroblastic oncogene B) amplification, 19 CDK4 (cyclin-dependent kinase 4)-cyclin D1 signaling, 20 and most recently PD-1/PD-L1 pathway. [5][6][7]…”

“…Interestingly, they found that the density of CD3 in the tumor-associated immune infiltrate was significantly (P=.049) higher in patients who were alive than in those who died, suggesting the importance of an exuberant T-cell response for survival in EMPD. 5 A third study investigated protein expression of the B7 family members as well as PD-1 and PD-L1/2 in 55 EMPD samples. In this study the authors also found that tumor cell PD-L1 was minimal.…”

“…The interaction between the programmed cell death receptor 1 (PD-1) and its ligand (PD-L1) is one of the pathways recently studied and has been reported to be a potential target in EMPD. [5][6][7] Programmed cell death receptor 1 signaling constitutes an immune checkpoint pathway that regulates the activation of tumor-specific T cells. 8 In several malignancies, cancer cells express PD-L1 on their surface to activate PD-1 signaling in T cells as a mechanism to dampen the tumor-specific immune response and evade antitumor immunity.…”