PD-L1 expression in pancreaticobiliary adenosquamous carcinoma: a single-institution case series

Abstract

Background: The programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is a potent negative regulator of T-cell-mediated immune response that is upregulated in many neoplasms. Pancreaticobiliary adenosquamous carcinoma (PB-ASC) is an aggressive cancer that carries a poorer prognosis compared with pure pancreaticobiliary adenocarcinoma (PB-AC). To date, there is little published information regarding PD-L1 expression in PB-ASC. The aim of the study was to examine the relationship between PD-L1 expression and tumor-infiltrating lymphocytes in PB-ASC and PB-AC.

Methods: We evaluated 15 PB-ASCs (10 pancreatic, 5 gallbladder) and 34 control PB-ACs (22 pancreatic ductal, and 12 gallbladder) for tumor expression of PD-L1 using anti-PD-L1 (E1L3N) antibody. All tumors were classified into three immune phenotypes: immune inflamed (II), immune excluded (IE), and immune desert (ID) according to the distribution of tumor-infiltrating lymphocytes in tumor tissues.

Results: The frequency of PD-L1 expression was significantly higher in PB-ASC (10/15; 66.7%) than in PB-AC (3/34; 8.8%). In PB-ASC, PD-L1 expression occurred exclusively in the squamous component in six cases, exclusively in the glandular component in one case, and in both the squamous and the glandular components in three cases. PD-L1 expression in PB-ASC was irrespective of the tumor immune status, whereas its expression in PB-AC was observed only in tumors with the II or IE phenotype. The ID phenotype was relatively rare (4/15; 26.7%) in PB-ASC compared with PB-AC (22/34; 65%; P=0.02).

Conclusions: PB-ASCs are notably enriched in inflammatory response and showed significantly higher PD-L1 expression than PB-AC (P<0.001), suggesting a potential therapeutic role for immune checkpoint inhibitors in managing patients with PB-ASC.

Keywords: Pancreaticobiliary carcinoma; adenosquamous carcinoma (ACC); programmed cell death ligand 1 (PD-L1); squamous differentiation; tumor-infiltrating lymphocytes (TILs).

Figure 1

PD-L1 expression status in PB-ASCs and PB-ACs. PD-L1, programmed cell death ligand 1; PB-ASC, pancreaticobiliary adenosquamous carcinoma; PB-AC, pancreaticobiliary adenocarcinoma.

Figure 2

PD-L1 expression in pancreatic adenosquamous carcinoma with the immune inflamed phenotype (case 8). (A) Glandular/adenocarcinoma component with innumerable stromal and intraepithelial tumor-infiltrating lymphocytes (H&E stained, magnification ×100), many of which are CD8-positive (inset, magnification ×200). (B) Squamous cell carcinoma component with many scattered intraepithelial lymphocytes (H&E stained, magnification ×100), which was confirmed by CD8 immunostaining (inset, magnification ×200). (C) Representative high-power views of membranous PD-L1 expression on tumor cells of the adenocarcinoma component (PD-L1 immunostain, magnification ×200). (D) Squamous cell carcinoma component showing clear circumferential membranous staining for PD-L1 (PD-L1 immunostain, magnification ×200). PD-L1, programmed cell death ligand 1; H&E, hematoxylin and eosin.

Figure 3

PD-L1 expression in a case of gallbladder adenosquamous carcinoma with the immune inflamed phenotype (case 15). (A) Adenocarcinoma component with relatively sparse intraepithelial lymphocytes (H&E stained, magnification ×100); infiltrating lymphocytes are positive for CD8 (inset, magnification ×200). (B) Squamous cell carcinoma component (H&E stained, magnification ×100) with many CD8-positive intraepithelial lymphocytes (inset, magnification ×200). (C) The adenocarcinoma component showed no membranous staining for PD-L1 (PD-L1 immunostain, magnification ×200). (D) Approximately 60% of the squamous area in this case showed clear immunoreactivity for PD-L1 (PD-L1 immunostain, magnification ×200). PD-L1, programmed cell death ligand 1; H&E, hematoxylin and eosin.

Figure 4

Host immune response to tumor cells in PB-ASCs and PB-ACs. PB-ASC, pancreaticobiliary adenosquamous carcinoma; PB-AC, pancreaticobiliary adenocarcinoma; II, immune inflamed; IE, immune exclusive; ID, immune desert.