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Changes in the frequency of myeloid-derived suppressor cells after transarterial chemoembolization with gelatin sponge microparticles for hepatocellular carcinoma

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Journal of Interventional Medicine 2019年第1期2卷 21-26页

作者： Yuanxun Yue Zhizhong Ren Ying Liu Yuewei Zhang Zhongshan Clinical College of Dalian University DalianLiaoning ProvincePeople's Republic of China Hepatobiliary Interventional Department Beijing Tsinghua Chang Gung Hospital Affiliated to Tsinghua UniversityBeijingPeople's Republic of China

Purpose: A series of clinical studies have established the safety and efficacy of transcatheter arterial chemoembolization(TACE) with gelatin sponge microparticles(GSMs) in treating hepatocellular carcinoma(HCC). HCC can lead to obvious necrosis inside tumors, especially larger ones, although it is unclear whether such necrotic tumor tissue can induce favorable immune reactions against the tumor. myeloid-derived suppressor cells(MDSCs)have immunosuppressive functions and are currently considered a very important cell type affecting tumor immunity. This study observed changes in MDSC frequency in peripheral blood before and after GSM–TACE to evaluate the effect on the immune function of HCC ***: Eight patients diagnosed with HCC underwent GSM–TACE treatment in the Hepatobiliary Interventional Department of Beijing Tsinghua Chang Gung Hospital, Beijing, China;we followed up with the patients over a period of 30 days post-surgery. We used flow cytometry(FCM) to quantify the frequency of MDSCs in peripheral blood before TACE, 10 days after surgery and 30 days after ***: MDSC frequency after GSM–TACE had a significant downward trend. Pre-TACE, it was 30.73% ? 11.93%,decreasing to 18.60% ? 11.37% at 10 days after operation. This decrease was not statistically significant(P > 0.05). MDSC frequency was even lower 30 days after TACE(7.63% ? 7.32%) than at 10 days after TACE(P < 0.05), and there was a significant difference compared with pre-TACE(P < 0.001). We evaluated tumor response at 30 days after GSM–TACE according to the Modified Response Evaluation Criteria in Solid Tumors(mRECIST), and all eight patients showed partial response(PR).Conclusion: Our results confirmed that GSM–TACE was beneficial for improving anti-tumor immunity in the treatment of HCC.

关键词： Gelatin sponge microparticles–transcatheter arterial chemoembolization(GSMs-TACE) Hepatocellular carcinoma myeloid-derived suppressor cells(MDSCs) Immunology

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GM3-containing nanoparticles in immunosuppressed hosts:Effect on myeloid-derived suppressor cells

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World Journal of Immunology 2014年第2期4卷 98-106页

作者： Audry Fernández Liliana Oliver Rydell Alvarez Luis E Fernández Circe Mesa Immunobiology Division Center of Molecular Immunology Innovation Division Center of Molecular Immunology

Cancer vaccines to date have not broadly achieved a significant impact on the overall survival of patients. The negative effect on the immune system of the tu-mor itself and conventional anti-tumor treatments such as chemotherapy is, undoubtedly, a key reason for these disappointing results. myeloid-derived suppres-sor cells （MDSCs） are considered a central node of the immunosuppressive network associated with tumors. These cells inhibit the effector function of natural killer and CD8＋ T cells, expand regulatory T cells and can differentiate into tumor-associated macrophages within the tumor microenvironment. Thus, overcoming the suppressive effects of MDSCs is likely to be criti-cal for cancer immunotherapy to generate effective anti-tumor immune responses. However, the capacity of cancer vaccines and particularly their adjuvants to overcome this inhibitory population has not been well characterized. Very small size proteoliposomes （VSSP） is a nanoparticulated adjuvant specifcally designed to be formulated with vaccines used in the treatment of immunocompromised patients. This adjuvant contains immunostimulatory bacterial signals together with GM3 ganglioside. VSSP promotes dendritic cell maturation, antigen cross-presentation to CD8＋ T cells, Th1 polar-ization, and enhances CD8＋ T cell response in tumor-free mice. Currently, four cancer vaccines using VSSP as the adjuvant are in Phase？Ⅰ？and Ⅱ clinical trials. In this review, we summarize our work characterizing the unique ability of VSSP to stimulate antigen-specifc CD8＋ T cell responses in two immunocompromised sce-narios; in tumor-bearing mice and during chemother-apy-induced leukopenia. Particular emphasis has been placed on the interaction of these nanoparticles with MDSCs, as well as comparison with other cancer vac-cine adjuvants currently in preclinical or clinical studies.

关键词： Very small size proteoliposomes Adjuvants Tumors myeloid-derived suppressor cells Leukopenia Chemotherapy

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Lysosomal acid lipase is critical for myeloid-derived suppressive cell differentiation, development, and homeostasis

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World Journal of Immunology 2014年第2期4卷 42-51页

作者： Cong Yan Hong Du Center for Immunobiology Indiana University School of Medicine Department of Pathology and Laboratory Medicine Indiana University School of Medicine IU Simon Cancer Center Indiana University School of Medicine

Lysosomal acid lipase （LAL） cleaves cholesteryl esters （CE） and triglycerides （TG） to generate cholesterol and free fatty acid in lysosomes of cells. The down-stream metabolic products of fatty acids are ligands for activation of peroxisome proliferator-activated re-ceptor gamma （PPARγ）. Accumulation of CEs and TGs is resulted from lack of functional LAL in lysosomes of cells, especially in myeloid cells. One characteristic phenotype in LAL knock-out （ lal-/- ） mice is systemic elevation of myeloid-derived suppressive cells （MDSCs）. MDSCs infltrate into multiple distal organs, alter T cell development, and suppress T cell proliferation and lym-phokine production in lal-/- mice, which lead to severe pathogeneses in multiple organs. The gene transcrip-tional profle analysis in MDSCs from the bone marrow has identified multiple defects responsible for MDSCs malformation and malfunction in lal-/- mice, including G protein signaling, cell cycles, glycolysis metabolism, mitochondrial bioenergetics, mTOR pathway etc. In a sep-arate gene transcriptional profle analysis in the lung of lal-/- mice, matrix metalloproteinase 12 （MMP12） and apoptosis inhibitor 6 （Api6） are highly overexpressed due to lack of ligand synthesis for PPARγ. PPARγ nega-tively regulates MMP12 and Api6. Blocking the PPAR signaling by overexpression of a dominant negative PPARγ （dnPPARγ） form, or overexpressing MMP12 or Api6 in myeloid or lung epithelial cells in inducible transgenic mouse models results in elevated MDSCs and infammation-induced tumorigenesis. These stud-ies demonstrate that LAL and its downstream effectors are critical for MDSCs development, differentiation and malfunction.

关键词： Lysosomal acid lipase myeloid-derived sup-pressor cells Immunosuppression myeloid-derived suppressive cell development Hematopoiesis

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Emergence of immunotherapy as a novel way to treat hepatocellular carcinoma

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World Journal of Gastroenterology 2018年第17期24卷 1839-1858页

作者： Naofumi Mukaida Yasunari Nakamoto Division of Molecular Bioregulation Cancer Research Institute Kanazawa University Second Department of Internal Medicine Faculty of Medical Sciences University of Fukui

Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma(HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from noncancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.

关键词： natural killer T cell natural killer cell chimeric antigen receptor T cell T cell receptor cytokine-induced killer cell program death-1 cytotoxic lymphocyte antigen-4 regulatory T cell dendritic cell myeloid-derived suppressor cell PD-ligand 1 peptide vaccine tumor-associated antigen tumor infiltrating lymphocyte

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A Study of Zoledronic Acid as Neo-Adjuvant, Perioperative Therapy in Patients with Resectable Pancreatic Ductal Adenocarcinoma

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Journal of Cancer Therapy 2013年第3期4卷 797-803页

作者： Dominic E. Sanford Matthew R. Porembka Roheena Z. Panni Jonathan B. Mitchem Brian A. Belt Stacey M. Plambeck-Suess Goldie Lin David G. DeNardo Ryan C. Fields William G. Hawkins Steven M. Strasberg Craig Lockhart Andrea Wang-Gillam Simon Peter Goedegebuure David C. Linehan Alvin J. Siteman Cancer Center St. Louis USA Department of Medicine School of Medicine Washington University St. Louis USA Department of Surgery School of Medicine Washington University St. Louis USA

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by abundant granulocytic myeloid-derived suppressor cells (G-MDSC = CD45+/Lin﹣/CD33+/CD11b+/CD15+), which infiltrate tumors and suppress anti-tumor immunity. We have previously demonstrated in a murine model of PDAC that zoledronic acid (ZA) depletes G-MDSC resulting in decreased tumor growth and improved survival. We report here the results of a phase 1 clinical trial (NCT00892242) using ZA as neo-adjuvant, perioperative therapy in patients with non-metastatic, resectable pancreatic adenocarcinoma. Methods: Eligible PDAC patients received ZA (4 mg) IV 2 weeks prior to surgery. Patients then received 2 additional doses of ZA 4 weeks apart. Blood and bone marrow were obtained from patients prior to treatment with ZA and 3 months after surgery for analysis of G-MDSC by flow cytometry. Results: Twenty-three patients received pre-operative ZA with at least 6 months of follow-up. Only 15 PDAC patients had nonmetastatic PDAC, which was amenable to resection. ZA was well tolerated, and all adverse events were grade 1 or 2. The most common adverse events were fatigue, abdominal pain/discomfort, anorexia, and arthralgia. Of resected PDAC patients treated with ZA, 1- and 2-year overall survival (OS) was 85.7% and 33.3%, respectively, with a median OS of 18 months. This group had a 1- and 2-year progression-free survival (PFS) of 26.9% and 8.9%, respectively, with a median PFS of 12 months. The prevalence of G-MDSC was unchanged in the blood and bone marrow of PDAC patients pre- and post-treatment with ZA. Conclusion: ZA is safe and well tolerated as neo-adjuvant, peri-operative therapy in PDAC patients. In this small study, we did not observe a difference in OS or PFS compared to historical controls. Also, there was no difference in the prevalence of G-MDSC in the blood and bone marrow of PDAC patients pre- and post-treatment with ZA.

关键词： Pancreatic Cancer Zoledronic Acid myeloid-derived Suppressor Cells

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Hepatic immune tolerance induced by hepatic stellate cells

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World Journal of Gastroenterology 2015年第42期21卷 11887-11892页

作者： Ching-Chuan Hsieh Chien-Hui Hung Lina Lu Shiguang Qian Department of Surgery Chang Gung Memorial Hospital at Chiayi Graduate Institute of Clinical Medical Sciences Chang Gung University Department of Immunology Lerner Research Institute Transplantation Center Digestive Disease Institute Cleveland Clinic Department of General Surgery Transplantation Center Digestive Disease Institute Cleveland Clinic

The liver, which is a metabolic organ, plays a pivotal role in tolerance induction. Hepatic stellate cells(Hp SCs), which are unique non-parenchymal cells, exert potent immunoregulatory activity during cotransplantation with allogeneic islets effectively protecting the islet allografts from rejection. Multiple mechanisms participate in the immune tolerance induced by Hp SCs, including the marked expansion of myeloid-derived suppressor cells(MDSCs), attenuation of effector T cell functions and augmentation of regulatory T cells. Hp SC conditioned MDSC-based immunotherapy has been conducted in mice with autoimmune disease and the results show that this technique may be promising. This article demonstrates how Hp SCs orchestrate both innate immunity and adaptive immunity to build a negative network that leads to immune tolerance.

关键词： Hepatic stellate cells myeloid-derived suppressor

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Circulating hematopoietic stem and progenitor cells are myeloidbiased in cancer patients

Circulating hematopoietic stem and progenitor cells are myel...

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第九届全国免疫学学术大会

作者： Wen-Chao Wu Hong-Wei Sun Limin Zheng 中山大学肿瘤防治中心

Cancer is associated with a profound perturbation in myelopoiesis that results in the accumulation of myeloid-derived suppressor cells(MDSCs)to promote disease *** studies in mice suggest that tumor-derived factors could regulate the differentiation of hematopoietic stem and progenitor cells(HSPCs)in the bone marrow and subsequently contribute to dysregulation of ***,the nature and role of HPSCs in patients with cancer remain *** we show,in detailed studies of the peripheral blood from 133 untreated patients with seven different types of tumors,that the composition of circulating HSPCs was significantly altered in patients with solid *** frequencies of circulating granulocyte-monocyte progenitors(GMPs)were increased four to seven fold in all types of tumors examined,and the circulating hematopoietic precursors exhibited myeloid bias with a skew toward granulocytic differentiation in patients with solid *** myeloid precursors are selectively enriched in tumor tissues,and the high levels of circulating GMPs were positively correlated with disease *** using cord blood-derived CD34+cells,we developed an in vitro short-term culture model to effectively induce the rapid generation of *** found that,among the factors produced by various tumors,GM-CSF,granulocyte colony stimulating factor,and IL-6 could not only promote the myeloid-biased differentiation,but also induce the differentiation of myeloid precursors into functional *** next investigated the influence of tumors on the differentiation of HSPCs in hematopoietic niches Both the expression of CXCL12 on bone marrow cells and its concentration in BM serum of tumor bearing mice were dramatically down-regulated,indicating the BM niche and its ability to maintain HSPCs were *** findings suggest that the altered HSPCs may serve as an important link between dysregulated bone marrow hematopoiesis and accumulated MDSCs in patients with c

关键词： hematopoietic stem and progenitor cells myeloid-derived suppressor cells tumor environment bone marrow niche extramedullary hematopoiesis

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