Epithelial–Mesenchymal Transition Phenotype and Peritumoral Immune Cell Infiltration in Advanced Biliary Tract Cancer

Abstract

We evaluated the clinical implications of epithelial-mesenchymal transition (EMT) markers and peritumoral immune cell in ltration in patients with biliary tract cancer (BTC) treated with gemcitabine plus cisplatin (GemCis). Forty-ve patients with advanced BTC who received GemCis were included as the study population. We conducted multiplex immunohistochemistry and examined EMT markers and their correlations with immune cell in ltrate at the invasive tumor margin. Study population was subdivided into two groups: twenty-four patients with short-term survival (SS) and 21 with long-term survival (LS).The density of tumor cells expressing epithelial marker E-cadherin (E-cadherin + CK + ) at the invasive tumor margin tended to be higher in the LS group than in the SS group (p = 0.065). The density of tumor cells expressing mesenchymal marker vimentin (vimentin + CK + ) was signi cantly higher in the SS group than in the LS group (p = 0.021). Accordingly, the density of E-cadherin − vimentin + CK + cells was also signi cantly higher in the SS group (p = 0.020). The density of vimentin + CK + cells was positively correlated with FoxP3 + CD4 + regulatory T-cells (r = 0.29, p = 0.047). EMT-related features were enriched in BTC patients with poor survival outcomes and were associated with the immunosuppressive tumor microenvironment.

Peptidylarginine Deiminase Type 2 Predicts Tumor Progression and Poor Prognosis in Patients with Curatively Resected Biliary Tract Cancer

“…The involvement of EMT processes in cholangiocarcinoma has been proposed previously [ 36 , 37 ]. Moreover, consistent over-expression of EMT-related features has been shown to correlate with poor prognosis in advanced BTC [ 38 ].…”

Therapeutic significance of tumor microenvironment in cholangiocarcinoma: focus on tumor-infiltrating T lymphocytes

“…Conversely, one study has demonstrated that CD4 + T-cell infiltration at the tumor edge is significantly higher than in the tumor center in both ICCA and extrahepatic CCA (eCCA) [ 18 ]. The BTC tumor edge serves as the primary location for active infiltration by FOXP3 + CD4 + Tregs that express elevated levels of lymphocyte activation gene 3 ( LAG-3 ) and T cell immunoglobulin and mucin domain-containing protein 3 ( TIM3 ) [ 33 , 34 ]. Furthermore, a high density of FOXP3 – CD4 + Th cells at the tumor edge is independently associated with longer PFS and OS in patients undergoing palliative gemcitabine plus cisplatin treatment [ 33 ].…”

“…The BTC tumor edge serves as the primary location for active infiltration by FOXP3 + CD4 + Tregs that express elevated levels of lymphocyte activation gene 3 (LAG-3) and T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) [33,34]. Furthermore, a high density of FOXP3 -CD4 + Th cells at the tumor edge is independently associated with longer PFS and OS in patients undergoing palliative gemcitabine plus cisplatin treatment [33]. Conversely, another study has found no significant difference in the distribution of CD4 + T cells between the peritumoral and intratumoral regions [35].…”

“…In relation to the spatial allocation of FOXP3 + TILs within the peritumoral and intratumoral regions of CCA, Goeppert et al [18] discovered that these lymphocytes directly infiltrate the tumor mass in both ICCA and eCCA subtypes. Conversely, another study suggested that FOXP3 + TILs primarily reside in the peritumoral region [33]. One study has ascertained no discernible difference in the distribution of FOXP3 + TILs between the intratumoral and peritumoral regions [39].…”