Programmed death ligand-1, tumor infiltrating lymphocytes and HLA expression in Chinese extrahepatic cholangiocarcinoma patients: Possible immunotherapy implications

Abstract

Cholangiocarcinoma (CCA) is a rare cancer biliary tract malignancy which accounts for less than 3% of all gastrointestinal cancers diagnosed worldwide (1). The incidence of CAA is highest in Thailand, China, and other Asian populations, but is lowest in the western world, presumably reflecting differences in the exposure of genetic and other risk factors (2). Anatomically, CCA can be divided into intrahepatic or extrahepatic subtypes choosing second-order bile ducts as the point of separation (3). The majority of CCA are extrahepatic cholangiocarcinoma (eCCA), whereas Summary Immunotherapy might be an effective treatment in extrahepatic cholangiocarcinoma (eCCA), a tumor with extremely limited therapeutic options. Our study is to characterize the programmed death ligand-1 (PD-L1) protein expression and cancer microenvironment profiles in surgically resected eCCA samples. PD-L1 positivity was observed on tumor cells (32.3%) as well as on tumor-associated macrophages (74.2%). PD-L1 expression by eCCA correlated significantly with immune parameters such as intra-tumoral CD3+ tumor infiltrating lymphocytes (TILs) density (P = 0.002), intra-tumoral CD8+ TILs density (P < 0.001), and the expression pattern of human leukocyte antigen (HLA) class I (P < 0.001). Immunofluorescence showed that PD-L1 positive tumor cells were adjacent to PD-1 positive cells and the stroma covered with interferon-γ. Correlation with clinicopathological parameters and survival analyses revealed that PD-L1 positivity in eCCA was related to the absence of venous invasion (P = 0.030), improved overall survival (P = 0.020) and progressionfree survival (P = 0.011). HLA class I molecules defect, which is an important mechanism of immune evasion, was frequently observed in eCCA (50.0%) and was associated with a decreased number of intra-tumoral CD8+ TIL density (P = 0.028). Additionally, the presence of unusually high numbers of tumor-associated macrophages (TAMs) subsets M2 in most of eCCA (74.2%) was noted. Our study indicated that PD-L1 expression in association with intra-tumoral TILs infiltration and HLA class I expression in 32.3% of the eCCA reflects an active immune microenvironment potentially responsive to PD-1/PD-L1 inhibitors. In addition, the combination of macrophage-targeting agents may provide therapeutic synergy for future immunotherapy.

Prognostic and Clinicopathological Significance of PD-L1 in Patients with Cholangiocarcinoma: A Meta-Analysis

“…The basic characteristics of the eligible studies are shown in Table 1. Seven studies were conducted in China [13,15,16,21,22,27,28], three in Japan [18,24,25], two in Korea [11,20], two in Germany [19,26], two in Germany [14,17], and one in Thailand [23] and UK [12]. One study was of prospective design [12], and 17 were retrospective cohort studies [11,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28].…”

“…Analysis. Seventeen studies [11][12][13][14][16][17][18][19][20][21][22][23][24][25][26][27][28] with a total of 1982 patients reported a correlation between PD-L1 and OS. The pooled HR and 95% CI suggested that overexpression of PD-L1 was significantly correlated with worse OS (HR = 1:58, 95%CI = 1:30 − 1:92, p < 0:001) in patients with CCA ( Figure 2; Table 3).…”

“…The pooled HR and 95% CI suggested that overexpression of PD-L1 was significantly correlated with worse OS (HR = 1:58, 95%CI = 1:30 − 1:92, p < 0:001) in patients with CCA ( Figure 2; Table 3). For DFS, a total of 7 studies [11,12,15,20,21,27,28] with 896 patients provided the relevant data. The forest plot (Figure 3) showed that PD-L1 expression was not significantly correlated with DFS (HR = 1:03, 95%CI = 0:68 − 1:55, p = 0:895) ( Table 3).…”

“…Thirteen studies [11,13,16,18,19,[21][22][23][24][25][26][27][28] investigated the relationship between PD-L1 and the following eight clinicopathological factors: sex (male vs. female), tumor differentiation (poor vs. well/moderate), pN stage (III+IV vs. I+II), TNM stage (III+IV vs. I+II), vascular invasion (yes vs. no), perineural invasion (yes vs. no), age (>60 vs. ≤60), and tumor size (>5 cm vs. ≤5 cm). As shown in Figure 4, high PD-L1 expression was correlated with poor 3.4.…”

“…Recent evidence also showed the prognostic value of PD-L1 in different types of cancers [10]. The prognostic role of PD-L1 in CCA has also been investigated; however, data were inconsistent [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. Therefore, we conducted a meta-analysis to explore the prognostic and clinicopathologic roles of PD-L1 in patients with CCA.…”