Functional and Phenotypic Characterization of Tumor-Infiltrating Leukocyte Subsets and Their Contribution to the Pathogenesis of Hepatocellular Carcinoma and Cholangiocarcinoma

Abstract

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) represent the most common primary liver malignancies whose outcome is influenced by the immune response. In the present study, we evaluated the tumor-infiltrating leukocyte (TIL) populations in 21 HCC patients and 8 CCA patients by flow cytometry immediately after the surgical procedure. Moreover, CD4 + T cells, CD8 + T cells, monocytes, and macrophages were purified by cell sorting for further analysis of gene expression by quantitative reverse-transcription polymerase chain reaction. Regarding tumor-infiltrating macrophages, we observed a significantly higher expression of markers associated with M2 phenotype and a higher expression of PD-L1 in patients with HCC in comparison to CCA. In addition, for HCC patients, we found a significant increase in the expression of CD200R in macrophages from tumors that were in grade G3-G4 as compared to tumors in grade G1-G2. Besides, a significantly higher frequency of tumor-infiltrating lymphocytes, CD8 + CD56 + T cells, and natural killer cells was detected in HCC biopsies in comparison to CCA. In summary, this study has revealed functional and phenotypic differences in TIL cell subpopulations between CCA and HCC, as well as among different histopathological grades and tumor aggressiveness degrees, and it has provided evidence to better understand the tumor immune microenvironment of CCA and HCC.

Current and novel therapeutic opportunities for systemic therapy in biliary cancer

“…CCA is characterised by marked abundance of tumour stroma, a bioactive connective tissue that not only physically negatively influences drug delivery, but also cross-talks with cancer cells for the activation of a chemoresistant phenotype (123)(124)(125). The CCA stroma consists of cancer-associated endothelial cells, CAFs and inflammatory cells -including tumour-associated macrophages (TAMs), neutrophils, natural killer (NK) and T cells (126,127) -dispersed in a bioactive specialised extracellular matrix (ECM) (128). CAFs are mainly responsible for mediating the composition of the ECM and crosstalk with CCA cells by secreting paracrine factors such as TGF-β and platelet-derived growth factor (PDGF) (126).…”

Alternative Splicing-Based Differences Between Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma: Genes, Immune Microenvironment, and Survival Prognosis

“…But it should point that the differences between such two common histological types of PCL still dominate in major biological process. The immune microenvironment of HCC and ICC is quite different (49), and the role of alternative splicing in the formation of the immune microenvironment is worth exploring. After clustering by DEAS events, it is found that HCC and ICC have a common immune metabolic checkpoint TDO2 (50), which is consistent with the "cofactor metabolic process" that we have enriched in functions.…”

Treatment of advanced biliary tract cancers: from chemotherapy to targeted agents

“…BTCs are characterised by significant desmoplastic reactions orchestrated by stromal cells, and different types of immune cells infiltrate. The complex TME ecosystem is populated with a wide variety of cells, including cancer cells, cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells, tumourassociated macrophages (TAMs), TILs, tumour-associated neutrophils, natural killer cells, and many others [108,109] . TME has a significant role in shaping a chemoresistant phenotype.…”