Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted

/pdf/cholangiocarcinoma-2020-the-next-horizon-in-mechanisms-and-4ua2gtq2hw.pdf

Cholangiocarcinoma 2020: the next horizon in mechanisms and management

Myeloid-derived suppressor cells (MDSCs) are a heterogenic population of immature myeloid cells with immunosuppressive effects, which undergo massive expansion during tumor progression. These cells not only support immune escape directly but also promote tumor invasion via various non-immunological activities. Besides, this group of cells are proved to impair the efficiency of current antitumor strategies such as chemotherapy, radiotherapy, and immunotherapy. Therefore, MDSCs are considered as potential therapeutic targets for cancer therapy. Treatment strategies targeting MDSCs have shown promising outcomes in both preclinical studies and clinical trials when administrated alone, or in combination with other anticancer therapies. In this review, we shed new light on recent advances in the biological characteristics and immunosuppressive functions of MDSCs. We also hope to propose an overview of current MDSCs-targeting therapies so as to provide new ideas for cancer treatment.

/pdf/myeloid-derived-suppressor-cells-as-immunosuppressive-4qlc2zmj7y.pdf

Myeloid-derived suppressor cells as immunosuppressive regulators and therapeutic targets in cancer.

Acquired resistance to cancer immunotherapy: role of tumor-mediated immunosuppression

MicroRNAs (miRNAs) are small non-coding RNAs, 18–23 nucleotides long, which act as post-transcriptional regulators of gene expression. miRNAs are strongly implicated in the pathogenesis of many common diseases, including IBDs. This review aims to outline the history, biogenesis and regulation of miRNAs. The role of miRNAs in the development and regulation of the innate and adaptive immune system is discussed, with a particular focus on mechanisms pertinent to IBD and the potential translational applications.

https://gut.bmj.com/content/gutjnl/64/3/504.full.pdf

MicroRNAs: new players in IBD

The clinical responses observed following treatment with immune checkpoint inhibitors (ICIs) support immunotherapy as a potential anticancer treatment. However, a large proportion of patients cannot benefit from it due to resistance or relapse, which is most likely attributable to the multiple immunosuppressive cells in the tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSCs), a heterogeneous array of pathologically activated immature cells, are a chief component of immunosuppressive networks. These cells potently suppress T-cell activity and thus contribute to the immune escape of malignant tumors. New findings indicate that targeting MDSCs might be an alternative and promising target for immunotherapy, reshaping the immunosuppressive microenvironment and enhancing the efficacy of cancer immunotherapy. In this review, we focus primarily on the classification and inhibitory function of MDSCs and the crosstalk between MDSCs and other myeloid cells. We also briefly summarize the latest approaches to therapies targeting MDSCs. 

/pdf/myeloid-derived-suppressor-cells-an-emerging-target-for-3j7dcw0l.pdf

Myeloid-derived suppressor cells: an emerging target for anticancer immunotherapy

Diagnostic and prognostic value of circulating miR-21 for cancer: A systematic review and meta-analysis

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells that suppress T-cell activity in a tumor microenvironment. However, the suppressive function of MDSCs on B cells and its underlying mechanism remain unclear. Here, we show that in 4T1 breast cancer mice, a significantly increased number of MDSCs, in parallel with splenic B cells, are accumulated when compared to normal mice. In the presence of MDSCs, the surface molecules of B cells are remolded, with checkpoint-related molecules such as PD-1 and PD-L1 changing prominently. MDSCs also emerge as vital regulators in B-cell immune functions such as proliferation, apoptosis and the abilities to secrete antibodies and cytokines. Our study further identifies that MDSCs can transform normal B cells to a subtype of immuno- regulatory B cells (Bregs) which inhibit T-cell response. Furthermore, we identified a novel kind of Bregs with a specific phenotype PD-1-PD-L1+CD19+, which exert the greatest suppressive effects on T cells in comparison with the previously reported Bregs characterized as CD1d+CD5+CD19+, CD5+CD19+ and Interleukin (IL)-10-secreting B cells. Our results highlight that MDSCs regulate B-cell response and may serve as a therapeutic approach in anti-tumor treatment. Investigation of this new Breg subtype extends our understanding of regulation of T-cell response and sheds new light on anti-tumor immunity and immune therapy.

/pdf/a-novel-mdsc-induced-pd-1-pd-l1-b-cell-subset-in-breast-54cfmb7ec7.pdf

A novel MDSC-induced PD-1-PD-L1+ B-cell subset in breast tumor microenvironment possesses immuno-suppressive properties.

// Lin Zhang 1, 3, 4, * , Jian Wang 1, 3, 4, * , Feng Wei 1, 3, 4 , Kaiyuan Wang 1, 3, 4 , Qian Sun 1, 3, 4 , Fan Yang 2, 3, 4 , Hao Jin 1, 3, 4 , Yu Zheng 2, 3, 4 , Hua Zhao 1, 3, 4 , Limei Wang 1, 3, 4 , Wenwen Yu 1, 3, 4 , Xiying Zhang 1, 3, 4 , Yang An 1, 3, 4 , Lili Yang 1, 3, 4 , Xinwei Zhang 2, 3, 4 , Xiubao Ren 2, 3, 4 1 Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tiyuanbei, Tianjin, China 2 Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China 3 National Clinical Research Center of Cancer, Tianjin, China 4 Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China * These authors contributed equally to this work as co-first authors Correspondence to: Xiubao Ren, email: renxiubao@tjmuch.com Keywords: checkpoint molecule, cytokine-induced killer cell (CIK), non-small-cell lung cancer (NSCLC), immunotherapy Received: January 19, 2016      Accepted: May 12, 2016      Published: June 07, 2016 ABSTRACT Immune checkpoints associate with dysfunctional T cells, which have a reduced ability to clear pathogens or cancer cells. T-cell checkpoint blockade may improve patient survival. However, checkpoint molecules on cytokine-induced killer (CIK) cell, a non-specific adoptive immunotherapy, remain unknown. In present study, we detected the dynamic expression of eight major checkpoint molecules (CTLA-4, PD-1, PD-L1, TIM-3, CEACAM-1, LAG-3, TIGIT and BTLA) on CIK cells from NSCLC patients. The majority of these molecules, except BTLA, were sharply elevated during the early stage of CIK cell culture. Thereafter, PD-1 and TIGIT expressions decreased gradually towards the initial level (day 0). Moreover, CTLA-4 faded away during the later stage of CIK culture. LAG-3 expression decreased but was still significantly higher than the initial level. Of note, PD-L1 remained stably upregulated during CIK culture compared with PD-1, indicating that PD-L1 might act as an inhibitory molecule on CIK cells instead of PD-1. Furthermore, TIM-3 and CEACAM1 were strongly expressed simultaneously during long-term CIK culture and showed a significant and mutually positive correlation. BTLA displayed a distinct pattern, and its expression gradually decreased throughout the CIK culture. These observations suggested that CIK cells might be partly exhausted before clinical transfusion, characterized by the high expression of PD-L1, LAG-3, TIM-3, and CEACAM-1 and the low expression of TIGIT, BTLA, PD-1, and CTLA-4 compared with initial culture. Our results imply that implementing combined treatment on CIK cells before transfusion via antibodies targeting PD-L1, LAG-3, TIM-3, and CEACAM-1 might improve the efficiency of CIK therapy for NSCLC patients.

Profiling the dynamic expression of checkpoint molecules on cytokine-induced killer cells from non-small-cell lung cancer patients

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Papers

Diagnostic and prognostic value of circulating miR-21 for cancer: A systematic review and meta-analysis

A novel MDSC-induced PD-1-PD-L1+ B-cell subset in breast tumor microenvironment possesses immuno-suppressive properties.

Profiling the dynamic expression of checkpoint molecules on cytokine-induced killer cells from non-small-cell lung cancer patients