Prognostic value of tumor-infiltrating lymphocytes (TILs) and expression of PD-L1 in cholangiocarcinoma.

Abstract

294 Background: Cholangiocarcinoma is a malignancy arising from the epithelial cells of the biliary tract with poor prognosis. Tumor-infiltrating lymphocytes (TILs) have a prognostic impact in various solid tumors. We aimed to investigate TIL expression and programmed cell death ligand PD-L1 and their clinical relevance in cholangiocarcinoma. Methods: Formalin-fixed paraffin-embedded tumor samples from thirty seven patients with resected and histologically verified cholangiocarcinoma between 1990 and 2011 were identified and immunohistochemically (IHC) stained with anti CD8, anti CD45RO and the anti-PDL1 mouseIgG1 (clone 5H1; Thompson) antibodies on a Leica automated IHC platform. The stains were semiquantitatively analyzed using the AllRed score system (range 1 to 8). Cases with IHC score > 3 were considered positive. The association between PDL1, CD45R0, overall survival (OS) and progressive free survival (PFS) was investigated using Kaplan-Meier survival and COX proportional hazard regression analyses. Results: The median age of patients was 64 (41-85) with 51% male. 25%, 59%, 10% and 5% were stage I, II, III, and IV respectively. CD8 was positive in 10/37 (27%) with median IHC of 5, CD45R0 (specimen with lymph node like structure) was positive in 16/37 (43%) with median IHC score of 4, PD-L1 was positive in 35/37 (94 %) with median IHC score of 8. Pts with tumors exhibiting lymph node (LN) like structures (CD45RO+) has better median OS (63 months vs 18 months, P = 0.0065) and median PFS (29 months vs 14.6 months, P = 0.05) than patients lacking LN like structures (CD45RO-). 5 yrs. OS in CD45RO+ was 64% vs 20% in CD45RO- (P 0.006) whereas 5 yrs. PFS in CD45RO+ was 41% vs. 8% in in CD45RO- pts (P value 0.05). Correlating PDL1 with OS and PFS was not done due to high expression of PD-L1 in most of the samples (94%). Conclusions: Presence of lymph node like structures (CD45RO+) was associated with significant better outcome reflecting the immune-mediated killing of tumor cells. The high expression of PD-L1 on cholangiocarcinoma cells represents a potential therapeutic target which may improve the prognosis for this dismal cancer. Future trials involving PD-L1 inhibitors in cholangiocarcinoma are warranted.

PD-1 and PD-L1 blockade in gastrointestinal malignancies

“…PD-L1 expression is found in a number of GI tumour types, suggesting this may be a possible biomarker [7,17,30,[37][38][39][40][41][42][43]. However, although PD-L1 expression on IHC has been correlated with prognosis and response in several studies [2,[7][8][9]30,37], other studies demonstrated efficacy in patients deemed PD-L1 negative [44], therefore the true relationship between PD-L1 expression and outcome is yet to be established.…”

“…One possible antibody for detecting PD-L1 expression on IHC is the murine antihuB7-H1, clone 5H1 (mAb5H1) [2,43]. This antibody can detect the PD-L1 (B7-H1) protein on the cell surface of frozen tissue sections [8,47].…”

“…An additional re-naturation step is required when using mAb5H1 for formalin-fixed paraffinembedded (FFPE) tissue [8]. Several studies have used mAb5H1 for their staining [2,8,9,43] and a Leica automated IHC platform can be used [43]. Investigators in the KEYNOTE-012 trial assessed PD-L1 expression in archival tumour samples using an investigational IHC assay employing the 22CE antibody [48,49].…”

“…In gastric cancer, the KEYNOTE-012 trial (NCT01848834) categorised PD-L1 positivity as archival tumour PD-L1 staining in the stroma or in at least 1% of tumour cells [48,49,51]. In cholangiocarcinoma patients, PD-L1 positivity was categorised as a value of >3 on semi-quantitative analysis using an ALLRed score system ranging from 1 to 8; 94% (35 of 37) of cholangiocarcinoma patients in this analysis were PD-L1 positive with an IHC score of 8 [43].…”

High ratio of programmed cell death protein 1 (PD-1)+/CD8+ tumor-infiltrating lymphocytes identifies a poor prognostic subset of extrahepatic bile duct cancer undergoing surgery plus adjuvant chemoradiotherapy

“…Several studies have demonstrated that the activity of PD-1 and/or PD-L1 was associated with patients' prognoses [18][19][20], but others could not validate the significance [21,22]. Until now, in bile duct cancer, two published studies and one abstract have analyzed the immunohistochemical results of PD-1 and/or PD-L1 [23][24][25]. However, the role of the immune checkpoint in patients' prognoses is not known yet.…”