Crosstalk between cancer cell plasticity and immune microenvironment in cholangiocarcinoma

Cholangiocarcinoma (CCA) is a highly aggressive tumor of the biliary tree characterized by an intense desmoplastic tumor microenvironment (TME). To date, treatment of CCA remains challenging; tumor resection is the only curative treatment with a high recurrence probability. Besides resection, therapeutic options have moved forward with the advent of immunotherapies, but these remain limited and low effective. Our knowledge about the cellular interplays in CCA is still fragmentary. An area is currently emerging regarding the potential role of cancer cell plasticity in the genesis of an immunosuppressive microenvironment. The cancer cells’ ability to acquire stemness properties and to disseminate through an epithelial-mesenchymal transition (EMT) shape a tumor immune microenvironment that supports cancer progression by attracting immunosuppressive cells including myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), M2 macrophages, and by increasing the expression of inhibitory immune checkpoints such as PD-1/PD-L-1. EMT-inducing transcription factors (EMT-TF) have recently emerged as regulators of tumor immunity by creating an immunosuppressive microenvironment. This review delves into the molecular mechanisms underlying the existing links between EMT/stemness and tumor immune microenvironment, as well as the last discoveries in CCA.

[1]  M. Mirian,et al.  Targeting vimentin: a multifaceted approach to combatting cancer metastasis and drug resistance , 2023, Cancer metastasis reviews.

[2]  P. J. Eichhorn,et al.  TGF-β, EMT, and resistance to anti-cancer treatment. , 2023, Seminars in cancer biology.

[3]  C. Blanpain,et al.  Cancer cell plasticity during tumor progression, metastasis and response to therapy , 2023, Nature Cancer.

[4]  C. Xie,et al.  Reciprocal Interaction of Cancer Stem Cells of Cholangiocarcinoma with Macrophage , 2023, Stem Cell Reviews and Reports.

[5]  J. Valle,et al.  Immunobiology of Cholangiocarcinoma. , 2023, Journal of hepatology.

[6]  P. ten Dijke,et al.  Harnessing epithelial-mesenchymal plasticity to boost cancer immunotherapy , 2023, Cellular & Molecular Immunology.

[7]  R. Schwabe,et al.  Immunology and immunotherapy of cholangiocarcinoma , 2023, Nature Reviews Gastroenterology & Hepatology.

[8]  F. Sipos,et al.  Cancer Stem Cell Relationship with Pro-Tumoral Inflammatory Microenvironment , 2023, Biomedicines.

[9]  Jing Yang,et al.  Regulation of epithelial-mesenchymal transition by tumor microenvironmental signals and its implication in cancer therapeutics , 2022, Seminars in cancer biology.

[10]  Saran Kumar,et al.  Cancer Plasticity: Investigating the causes for this agility. , 2022, Seminars in cancer biology.

[11]  Xiaoming Huang,et al.  SHH/GLI2-TGF-β1 feedback loop between cancer cells and tumor-associated macrophages maintains epithelial-mesenchymal transition and endoplasmic reticulum homeostasis in cholangiocarcinoma. , 2022, Pharmacological research.

[12]  K. Mortezaee,et al.  Cancer stem cells in immunoregulation and bypassing anti-checkpoint therapy. , 2022, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[13]  Hang Zheng,et al.  Characterization of stem cell landscape and identification of stemness-relevant prognostic gene signature to aid immunotherapy in colorectal cancer , 2022, Stem cell research & therapy.

[14]  Guanghui Yang,et al.  Macrophages Are a Double-Edged Sword: Molecular Crosstalk between Tumor-Associated Macrophages and Cancer Stem Cells , 2022, Biomolecules.

[15]  R. Schwabe,et al.  Novel microenvironment-based classification of intrahepatic cholangiocarcinoma with therapeutic implications , 2022, Gut.

[16]  S. Boyault,et al.  Epithelial-to-mesenchymal transition promotes immune escape by inducing CD70 in non-small cell lung cancer. , 2022, European journal of cancer.

[17]  F. Escorcia,et al.  Characterization of Immunogenicity of Malignant Cells with Stemness in Intrahepatic Cholangiocarcinoma by Single-Cell RNA Sequencing , 2022, Stem cells international.

[18]  G. Wang,et al.  Mechanism of cancer stemness maintenance in human liver cancer , 2022, Cell death & disease.

[19]  Ruibin Xi,et al.  Single-cell transcriptomic analysis suggests two molecularly distinct subtypes of intrahepatic cholangiocarcinoma , 2022, Nature Communications.

[20]  Ben Ma,et al.  Novel Stemness-Related Gene Signature Predicting Prognosis and Indicating a Different Immune Microenvironment in HNSCC , 2022, Frontiers in Genetics.

[21]  C. Caux,et al.  ZEB1 transcription factor promotes immune escape in melanoma , 2022, Journal for ImmunoTherapy of Cancer.

[22]  D. Hua,et al.  Biochanin A Suppresses Tumor Progression and PD-L1 Expression via Inhibiting ZEB1 Expression in Colorectal Cancer , 2022, Journal of oncology.

[23]  Ritu Shrestha,et al.  CD73 and PD-L1 as Potential Therapeutic Targets in Gallbladder Cancer , 2022, International Journal of Molecular Sciences.

[24]  A. Khattri,et al.  Pan-Cancer Analysis Shows Enrichment of Macrophages, Overexpression of Checkpoint Molecules, Inhibitory Cytokines, and Immune Exhaustion Signatures in EMT-High Tumors , 2022, Frontiers in Oncology.

[25]  Y. Miyamoto,et al.  Association of PD-L1 and ZEB-1 expression patterns with clinicopathological characteristics and prognosis in oral squamous cell carcinoma. , 2022, Oncology letters.

[26]  L. Tian,et al.  Macrophages-aPKCɩ-CCL5 Feedback Loop Modulates the Progression and Chemoresistance in Cholangiocarcinoma , 2021, Journal of Experimental & Clinical Cancer Research.

[27]  Yuli Lin,et al.  CAFs shape myeloid‐derived suppressor cells to promote stemness of intrahepatic cholangiocarcinoma through 5‐lipoxygenase , 2021, Hepatology.

[28]  V. Paradis,et al.  Zinc Finger E‐Box Binding Homeobox 1 Promotes Cholangiocarcinoma Progression Through Tumor Dedifferentiation and Tumor–Stroma Paracrine Signaling , 2021, Hepatology.

[29]  D. Dean,et al.  Zeb1 induces immune checkpoints to form an immunosuppressive envelope around invading cancer cells , 2021, Science Advances.

[30]  M. Abbaszadegan,et al.  Correlation between the immune checkpoints and EMT genes proposes potential prognostic and therapeutic targets in ESCC , 2021, Journal of Molecular Histology.

[31]  N. Matsumura,et al.  Tumor Immune Microenvironment during Epithelial–Mesenchymal Transition , 2021, Clinical Cancer Research.

[32]  T. Tan,et al.  Epithelial to Mesenchymal Transition Regulates Surface PD-L1 via CMTM6 and CMTM7 Induction in Breast Cancer , 2021, Cancers.

[33]  C. Yau,et al.  The Oxford Classic Links Epithelial-to-Mesenchymal Transition to Immunosuppression in Poor Prognosis Ovarian Cancers , 2021, Clinical Cancer Research.

[34]  L. Kowalski,et al.  Co-Overexpression of TWIST1-CSF1 Is a Common Event in Metastatic Oral Cancer and Drives Biologically Aggressive Phenotype , 2021, Cancers.

[35]  R. Weinberg,et al.  Direct and Indirect Regulators of Epithelial-Mesenchymal Transition (EMT)-mediated Immunosuppression in Breast Carcinomas. , 2020, Cancer discovery.

[36]  G. Gores,et al.  Cholangiocarcinoma 2020: the next horizon in mechanisms and management , 2020, Nature Reviews Gastroenterology & Hepatology.

[37]  Yuan Zhang,et al.  Single cell transcriptomic architecture and intercellular crosstalk of human intrahepatic cholangiocarcinoma. , 2020, Journal of hepatology.

[38]  M. Fares,et al.  Molecular principles of metastasis: a hallmark of cancer revisited , 2020, Signal Transduction and Targeted Therapy.

[39]  A. Gentles,et al.  MYC and Twist1 cooperate to drive metastasis by eliciting crosstalk between cancer and innate immunity , 2020, eLife.

[40]  P. Pineau,et al.  Identification of Four Immune Subtypes Characterized by Distinct Composition and Functions of Tumor Microenvironment in Intrahepatic Cholangiocarcinoma , 2019, Hepatology.

[41]  Juliette Paillet,et al.  Immune contexture of cholangiocarcinoma. , 2019, Current opinion in gastroenterology.

[42]  Wei Yang,et al.  MHC class I dysfunction of glioma stem cells escapes from CTL-mediated immune response via activation of Wnt/β-catenin signaling pathway , 2019, Oncogene.

[43]  P. Chu,et al.  Role of Cancer Stem Cells in Cholangiocarcinoma and Therapeutic Implications , 2019, International journal of molecular sciences.

[44]  M. Smid,et al.  Epithelial-Mesenchymal Transition in Human Prostate Cancer Demonstrates Enhanced Immune Evasion Marked by IDO1 Expression. , 2018, Cancer research.

[45]  C. Desbois-Mouthon,et al.  The IGF2/IR/IGF1R Pathway in Tumor Cells and Myofibroblasts Mediates Resistance to EGFR Inhibition in Cholangiocarcinoma , 2018, Clinical Cancer Research.

[46]  Masafumi Nakamura,et al.  Combined Gemcitabine and Metronidazole Is a Promising Therapeutic Strategy for Cancer Stem-like Cholangiocarcinoma. , 2018, Anticancer research.

[47]  N. Matsumura,et al.  Snail promotes ovarian cancer progression by recruiting myeloid-derived suppressor cells via CXCR2 ligand upregulation , 2018, Nature Communications.

[48]  Yan Liu,et al.  aPKC‐ι/P‐Sp1/Snail signaling induces epithelial–mesenchymal transition and immunosuppression in cholangiocarcinoma , 2017, Hepatology.

[49]  F. Azuaje,et al.  CD47 is a direct target of SNAI1 and ZEB1 and its blockade activates the phagocytosis of breast cancer cells undergoing EMT , 2017, Oncoimmunology.

[50]  R. Weinberg,et al.  Epithelial-to-Mesenchymal Transition Contributes to Immunosuppression in Breast Carcinomas. , 2017, Cancer research.

[51]  Yuli Lin,et al.  FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3-CCL2 Signaling. , 2016, Cancer research.

[52]  E. Ben-Jacob,et al.  Immunoproteasome deficiency is a feature of non-small cell lung cancer with a mesenchymal phenotype and is associated with a poor outcome , 2016, Proceedings of the National Academy of Sciences.

[53]  Jing Wang,et al.  Epithelial–Mesenchymal Transition Is Associated with a Distinct Tumor Microenvironment Including Elevation of Inflammatory Signals and Multiple Immune Checkpoints in Lung Adenocarcinoma , 2016, Clinical Cancer Research.

[54]  Jaime Rodriguez-Canales,et al.  A Patient-Derived, Pan-Cancer EMT Signature Identifies Global Molecular Alterations and Immune Target Enrichment Following Epithelial-to-Mesenchymal Transition , 2015, Clinical Cancer Research.

[55]  J. Xu,et al.  Transforming growth factor-β1-induced epithelial-mesenchymal transition generates ALDH-positive cells with stem cell properties in cholangiocarcinoma. , 2014, Cancer letters.

[56]  Chun-Hung Chou,et al.  Acetylation of snail modulates the cytokinome of cancer cells to enhance the recruitment of macrophages. , 2014, Cancer cell.

[57]  Lixia Diao,et al.  Metastasis is regulated via microRNA-200/ZEB1 axis control of tumor cell PD-L1 expression and intratumoral immunosuppression , 2014, Nature Communications.

[58]  T. Tan,et al.  Epithelial-to-mesenchymal transition and autophagy induction in breast carcinoma promote escape from T-cell-mediated lysis. , 2013, Cancer research.

[59]  N. Van Rooijen,et al.  Twist1 induces CCL2 and recruits macrophages to promote angiogenesis. , 2013, Cancer research.

[60]  Yutaka Kawakami,et al.  CCL2 is critical for immunosuppression to promote cancer metastasis , 2012, Clinical & Experimental Metastasis.

[61]  Didier Samuel,et al.  Identification of Cellular Targets in Human Intrahepatic Cholangiocarcinoma Using Laser Microdissection and Accurate Mass and Time Tag Proteomics* , 2010, Molecular & Cellular Proteomics.

[62]  F. Marincola,et al.  Immunobiological Characterization of Cancer Stem Cells Isolated from Glioblastoma Patients , 2010, Clinical Cancer Research.

[63]  Yutaka Kawakami,et al.  Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. , 2009, Cancer cell.

[64]  A. Sica,et al.  Cholangiocarcinoma stem-like subset shapes tumor-initiating niche by educating associated macrophages. , 2017, Journal of hepatology.

[65]  F. Giuliante,et al.  TUMORIGENESIS AND NEOPLASTIC PROGRESSION Pro fi les of Cancer Stem Cell Subpopulations in Cholangiocarcinomas , 2022 .