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

Abstract

Cholangiocarcinoma (CCA) is a highly aggressive type of adenocarcinoma distinguished by its invasiveness. Depending on specific anatomical positioning within the biliary tree, CCA can be categorized into intrahepatic CCA (ICCA), perihilar CCA (pCCA) and distal CCA (dCCA). In recent years, there has been a significant increase in the global prevalence of CCA. Unfortunately, many CCA patients are diagnosed at an advanced stage, which makes surgical resection impossible. Although systemic chemotherapy is frequently used as the primary treatment for advanced or recurrent CCA, its effectiveness is relatively low. Therefore, immunotherapy has emerged as a promising avenue for advancing cancer treatment research. CCA exhibits a complex immune environment within the stromal tumor microenvironment (TME), comprising a multifaceted immune landscape and a tumor-reactive stroma. A deeper understanding of this complex TME is indispensable for identifying potential therapeutic targets. Thus, targeting tumor immune microenvironment holds promise as an effective therapeutic strategy.

Keywords: Tumor microenvironment; cholangiocarcinoma; immunotherapy; molecular pathogenesis; tumor-infiltrating T lymphocytes.

Figure 1

Based on the relative anatomical location within the liver, CCA can be categorized into three types: ICCA, perihilar CCA (pCCA), and dCCA. ICCA is characterized by bile duct cancer within the liver, with histological subtypes including mass-forming, periductal infiltrating, and intraductal growing; pCCA refers to a secondary branch located in the hepatic duct, specifically from the common bile duct above the cystic duct to the liver, and is histologically classified as a klatskin tumor; dCCA denotes located outside the liver, primarily presenting as adenocarcinoma histologically. GBC: gallbladder cancer; FGFR2: fibroblast growth factor receptor 2

Figure 2

Dendritic cells (DCs) play a pivotal role in the activation of naive T cells through the process of antigen presentation via phagocytosis. Moreover, they are responsible for initiating immune responses, secreting chemotactic cytokines to attract T/B cells, and presenting antigens to CD8⁺/CD4⁺ T cells via major histocompatibility complex class I/II (MHC I/II) cells. Upon activation of CD8⁺ T cells, the release of perforin, granzymes and Fas cell surface death receptor (FAS)/Fas ligand (FASL) transmembrane glycoproteins lead to the eradication of tumors. The recruitment of CD8⁺ T cells and the expression of interferon-gamma (IFN-γ) were found to be hindered by inhibiting mutant isocitrate dehydrogenase 1 (mIDH1). Simultaneously, the expression of human leukocyte antigen class I (HLA I) facilitates the presentation of tumor antigen-derived peptides to the immune system, thereby eliciting anti-tumor effects through the activation of CD8⁺ T cells. The application of lentiviral transcription encoding short hairpin RNA (shRNA) to inhibit B7 homolog 4 (B7H4) has the potential to enhance CD8⁺ T-cell-mediated cytotoxicity. The potential of CD4⁺ T cells to elicit a response against the mutated ERBB2 interacting protein (ERBB2IP) antigen holds promise for inducing degeneration in metastatic epithelial cell carcinoma tissues. In vitro studies have shown that trametinib can upregulate of MHC I and programmed cell death ligand-1 (PDL1) on tumor cells. Furthermore, the combination of trametinib with anti-PDL1 drugs can increase the anti-tumor activity of hepatic effector memory CD4⁺ T cells. The upregulation of transforming growth factor beta 1 (TGF-β1) in neoplastic cells induces heterogeneity in regulatory T cells (Tregs) within the TME, which forms a milieu for the proliferation of tumor cells, inhibits apoptosis, and stimulates angiogenesis. This process ultimately facilitates tumor progression, but can be counteracted by the concurrent administration of gemcitabine in combination with carboplatin. The expression of leukocyte-associated immunoglobulin-like receptor-2 (LAIR2) by Tregs hinders the binding of LAIR1 to competing ligands, disrupts platelet activation and adhesion, and impedes the classical pathway of the complement system and the lectin pathway. As a result, LAIR2 inhibits the elimination of pathogens. CTLs: cytotoxic T lymphocytes; PD1: programmed cell death protein-1; Th: T helper

Figure 3

List of ICIs and their receptors in CCA. CEACAM: the carcinoembryonic antigen-related adhesion molecules; KIR: killer cell immunoglobulin like receptor; GITR: Glucocorticoid-Induced TNF-related protein; GITRL: GITR ligand; B7H4R: B7H4 receptor

Figure 4

Structure of CAR T. mAb: monoclonal antibody