Multimodal single-cell profiling of intrahepatic cholangiocarcinoma defines hyperactivated Tregs as a potential therapeutic target

Alvisi, Giorgia; Termanini, Alberto; Soldani, Cristiana; Portale, Federica; Carriero, Roberta; Pilipow, Karolina; Costa, Guido; Polidoro, Michela Anna; Franceschini, Barbara; Malenica, Ines; Puccio, Simone; Lise, Veronica; Galletti, G; Zanon, Veronica; Colombo, Federico; Simone, Gabriele De; Tufano, Michele; Aghemo, Alessio; Tommaso, Luca Di; Peano, Clelia; Cibella, Javier; Iannacone, Matteo; Roychoudhuri, Rahul; Manzo, Teresa; Donadon, Matteo; Torzilli, Guido; Kunderfranco, Paolo; Mitri, Diletta Di; Lugli, Enrico; Lleò, Ana

doi:10.1016/j.jhep.2022.05.043

Cited by 34 publications

(6 citation statements)

References 51 publications

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“…Previous studies have reported that M2 macrophage promote tumor invasion, progression and immune escape through increasing the expression of MHC class I molecules and secreting anti-inflammatory cytokines ( 29 – 31 ). Moreover, Tregs also inhibit the immune response, which led to immunosuppressive functions and accelerated the malignant tumors progression ( 32 , 33 ). Neutrophils secrete some factors, such anti-inflammation cytokines, to affect TME, promoting tumor occurrence and metastasis ( 34 , 35 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of copper metabolism and cuproptosis-related subtypes for predicting prognosis tumor microenvironment and drug candidates in hepatocellular carcinoma

et al. 2022

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Copper (Cu) is an essential element of organisms, which can affect the survival of cells. However, the role of copper metabolism and cuproptosis on hepatic carcinoma is still unclear. In this study, the TCGA database was used as the test set, and the ICGC database and self-built database were used as the validation set. We screened out a class of copper metabolism and cuproptosis-related genes (CMCRGs) that could influence hepatic carcinoma prognosis by survival analysis and differential comparison. Based on CMCRGs, patients were divided into two subtypes by cluster analysis. The C2 subtype was defined as the high copper related subtype, while the C1 subtype was defied as the low copper related subtype. At the clinical level, compared with the C1 subtype, the C2 subtype had higher grade pathological features, risk scores, and worse survival. In addition, the immune response and metabolic status also differed between C1 and C2. Specifically, C2 subtype had a higher proportion of immune cell composition and highly expressed immune checkpoint genes. C2 subtype had a higher TIDE score with a higher proportion of tumor immune dysfunction and exclusion. At the molecular level, the C2 subtype had a higher frequency of driver gene mutations (TP53 and OBSCN). Mechanistically, the single nucleotide polymorphisms of C2 subtype had a very strong transcriptional strand bias for C>A mutations. Copy number variations in the C2 subtype were characterized by LOXL3 CNV gain, which also showed high association with PDCD1/CTLA4. Finally, drug sensitivity responsiveness was assessed in both subtypes. C2 subtype had lower IC50 values for targeted and chemotherapeutic agents (sorafenib, imatinib and methotrexate, etc.). Thus, CMCRGs related subtypes showed poor response to immunotherapy and better responsiveness to targeted agents, and the results might provide a reference for precision treatment of hepatic carcinoma.

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Section: Discussionmentioning

confidence: 99%

Identification of copper metabolism and cuproptosis-related subtypes for predicting prognosis tumor microenvironment and drug candidates in hepatocellular carcinoma

et al. 2022

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“…Furthermore, a recent single-cell study, aimed at elucidating the molecular characteristics of immune cells in iCCA, revealed that B cells were among the most abundant immune cells in the tumor tissue and in the peritumoral tissue, after T cells, NK cells and myeloid cells. This study demonstrated the presence of lower levels of B cells in the tumor tissue compared to adjacent peritumoral tissue [ 119 ]. However, given the limited number of studies on B cells in CCA, their relevance in this type of cancer as well as their feasibility as a potential immunotherapeutic target have not been elucidated yet.…”

Section: Adaptive Immune Systemmentioning

confidence: 99%

Heterogeneity of Cholangiocarcinoma Immune Biology

Vita

Olaizola

Amato

et al. 2023

Cells

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Cholangiocarcinomas (CCAs) are aggressive tumors arising along the biliary tract epithelium, whose incidence and mortality are increasing. CCAs are highly desmoplastic cancers characterized by a dense tumor microenvironment (TME), in which each single component plays a fundamental role in shaping CCA initiation, progression and resistance to therapies. The crosstalk between cancer cells and TME can affect the recruitment, infiltration and differentiation of immune cells. According to the stage of the disease and to intra- and inter-patient heterogeneity, TME may contribute to either protumoral or antitumoral activities. Therefore, a better understanding of the effect of each immune cell subtype may open the path to new personalized immune therapeutic strategies for the management of CCA. In this review, we describe the role of immune cells in CCA initiation and progression, and their crosstalk with both cancer-associated fibroblasts (CAFs) and the cancer-stem-cell-like (CSC) niche.

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“…Their results revealed that the TME of these tumors is characterized by a low infiltration of tumor-specific CD8+ T cells, marked by CD39+, which is associated with a high infiltration of hyper-activated CD4+ regulatory T cells (Tregs). Tregs frequency compared to that of CD4+ CD69+ T cells and conventional type 2 dendritic cells was linked to a poor prognosis [ 37 ]. In another study, Zhang et al detected a diverse population of cancer-associated fibroblasts (CAFs), in which a predominant subpopulation of vascular CD146+ CAFs expressed high levels of IL-6, which in turn promoted tumor progression through IL-6R signaling on malignant cells [ 38 ].…”

Section: Tumor Microenvironment In Biliary Tract Tumorsmentioning

confidence: 99%

Targeting Angiogenesis in the Era of Biliary Tract Cancer Immunotherapy: Biological Rationale, Clinical Implications, and Future Research Avenues

Schirizzi

Leonardis

Lorusso

et al. 2023

Cancers

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Although biliary tract cancers are traditionally considered rare in Western countries, their incidence and mortality rates are rising worldwide. A better knowledge of the genomic landscape of these tumor types has broadened the number of molecular targeted therapies, including angiogenesis inhibitors. The role of immune checkpoint inhibitors (ICIs) could potentially change the first-line therapeutic approach, but monotherapy with ICIs has shown disappointing results in CCA. Several clinical trials are evaluating combination strategies that include immunotherapy together with other anticancer agents with a synergistic activity. The tumor microenvironment (TME) composition plays a pivotal role in the prognosis of BTC patients. The accumulation of immunosuppressive cell types, such as tumor-associated macrophages (TAMs) and regulatory T-cells, together with the poor infiltration of cytotoxic CD8+ T-cells, is known to predispose to a poor prognosis owing to the establishment of resistance mechanisms. Likewise, angiogenesis is recognized as a major player in modulating the TME in an immunosuppressive manner. This is the mechanistic rationale for combination treatment schemes blocking both immunity and angiogenesis. In this scenario, this review aims to provide an overview of the most recent completed or ongoing clinical trials combining immunotherapy and angiogenesis inhibitors with/without a chemotherapy backbone.

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Multimodal single-cell profiling of intrahepatic cholangiocarcinoma defines hyperactivated Tregs as a potential therapeutic target

Cited by 34 publications

References 51 publications

Identification of copper metabolism and cuproptosis-related subtypes for predicting prognosis tumor microenvironment and drug candidates in hepatocellular carcinoma

Identification of copper metabolism and cuproptosis-related subtypes for predicting prognosis tumor microenvironment and drug candidates in hepatocellular carcinoma

Heterogeneity of Cholangiocarcinoma Immune Biology

Targeting Angiogenesis in the Era of Biliary Tract Cancer Immunotherapy: Biological Rationale, Clinical Implications, and Future Research Avenues

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