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Rajkumari S, Singh J, Agrawal U, Agrawal S. Myeloid-derived suppressor cells in cancer: Current knowledge and future perspectives. Int Immunopharmacol 2024; 142:112949. [PMID: 39236460 DOI: 10.1016/j.intimp.2024.112949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 08/12/2024] [Accepted: 08/13/2024] [Indexed: 09/07/2024]
Abstract
MDSCs (myeloid-derived suppressor cells) are crucial for immune system evasion in cancer. They accumulate in peripheral blood and tumor microenvironment, suppressing immune cells like T-cells, natural killer cells and dendritic cells. They promote tumor angiogenesis and metastasis by secreting cytokines and growth factors and contribute to a tumor-promoting environment. The accumulation of MDSCs in cancer patients has been linked to poor prognosis and resistance to various cancer therapies. Targeting MDSCs and their immunosuppressive mechanisms may improve treatment outcomes and enhance immune surveillance by developing drugs that inhibit MDSC function, by preventing their accumulation and by disrupting the tumor-promoting environment. This review presents a detailed overview of the MDSC research in cancer with regulation of their development and function. The relevance of MDSC as a prognostic and predictive biomarker in different types of cancers, along with recent advancements on the therapeutic approaches to target MDSCs are discussed in detail.
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Affiliation(s)
- Sunanda Rajkumari
- ICMR National Institute of Medical Statistics, Ansari Nagar, New Delhi 110029, India
| | - Jaspreet Singh
- ICMR National Institute of Pathology, Safdarjung Hospital Campus, Ansari Nagar, New Delhi 110029, India
| | - Usha Agrawal
- Asian Institute of Public Health University (AIPH) University, 1001 Haridamada, Jatani, Near IIT Bhubaneswar, Bhubaneswar 751002, India
| | - Sandeep Agrawal
- Discovery Research Division, Indian Council of Medical Research, Ansari Nagar, New Delhi 110029, India.
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2
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Donaubauer AJ, Scheer I, Fietkau R, Gaipl US, Frey B. Flow cytometry-based monitoring of myeloid-derived suppressor cells in the peripheral blood of patients with solid tumors. Methods Cell Biol 2024; 191:135-150. [PMID: 39824553 DOI: 10.1016/bs.mcb.2024.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2025]
Abstract
Myeloid-derived suppressor cells (MDSCs) ameliorate inflammation by inhibiting T cell responses. In pathological conditions, such as autoimmunity, chronic infections or cancer they accumulate in the periphery. In cancer, MDSCs can also be part of the tumor microenvironment and are associated with a worse prognosis and limited response to immunotherapy. Nowadays attempts are made to specifically target MDSCs in cancer therapy. Still, the role of MDSCs in standard cancer treatment modalities, such as radiotherapy remains mostly elusive. Here, we describe a flow cytometry-based method to determine and monitor monocytic and granulocytic-derived MDSCs directly from whole blood in an easy, fast and reliable assay. As specific surface markers for MDSCs are lacking, the assay follows a gating strategy that excludes successively the main immune cells types and analyzes the remaining events for a set of molecules that are expressed on MDSCs. This assay is especially appropriate for longitudinal analyses and clinical trials and is suitable for being integrated into more complex immunophenotyping panels to generate a comprehensive immune status.
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Affiliation(s)
- Anna-Jasmina Donaubauer
- Translational Radiobiology, Department of Radiation Oncology, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
| | - Ilka Scheer
- Translational Radiobiology, Department of Radiation Oncology, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
| | - Rainer Fietkau
- Department of Radiation Oncology, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany; FAU Profile Center Immunomedicine (FAU I-MED), Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Schlossplatz 1, Erlangen, Germany
| | - Udo S Gaipl
- Translational Radiobiology, Department of Radiation Oncology, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany; FAU Profile Center Immunomedicine (FAU I-MED), Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Schlossplatz 1, Erlangen, Germany.
| | - Benjamin Frey
- Translational Radiobiology, Department of Radiation Oncology, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany; FAU Profile Center Immunomedicine (FAU I-MED), Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Schlossplatz 1, Erlangen, Germany
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Yue Y, Ren Z, Wang Y, Liu Y, Yang X, Wang T, Bai Y, Zhou H, Chen Q, Li S, Zhang Y. Impact of Microparticle Transarterial Chemoembolization (mTACE) on myeloid-derived suppressor cell subtypes in hepatocellular carcinoma: Clinical correlations and therapeutic implications. Immun Inflamm Dis 2024; 12:e70007. [PMID: 39222024 PMCID: PMC11367920 DOI: 10.1002/iid3.70007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 04/08/2024] [Accepted: 08/12/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Myeloid-derived suppressor cells (MDSCs) play a pivotal role in immunosuppression and tumor progression in hepatocellular carcinoma (HCC). While various treatments like surgical resection, ablation, and radiotherapy have been studied for their effects on circulating MDSC frequencies in HCC patients, the findings remain inconclusive. Transarterial Chemoembolization (TACE) stands as the standard care for unresectable HCC, with Microparticle TACE (mTACE) gaining prominence for its capacity to induce significant tumor necrosis. However, the immunological ramifications of such pathological outcomes are scarcely reported. METHODS AND RESULTS This study aims to elucidate the alterations in MDSC subtypes, specifically monocytic MDSCs (mMDSCs) and early-stage MDSCs (eMDSCs), post-mTACE and to investigate their clinical correlations in HCC patients. A cohort comprising 75 HCC patients, 16 liver cirrhosis patients, and 20 healthy controls (HC) was studied. Peripheral blood samples were collected and analyzed for MDSC subtypes. The study also explored the associations between MDSC frequencies and various clinical parameters in HCC patients. The frequency of mMDSCs was significantly elevated in the HCC group compared to liver cirrhosis and HC. Importantly, mMDSC levels were strongly correlated with aggressive clinical features of HCC, including tumor size, vascular invasion, and distant metastasis. Post-mTACE, a marked reduction in mMDSC frequencies was observed, while eMDSC levels remained stable. CONCLUSIONS Our findings underscore the critical role of mMDSCs in HCC pathogenesis and their potential as a therapeutic target. The study also highlights the efficacy of mTACE in modulating the immunosuppressive tumor microenvironment, thereby opening new avenues for combinatorial immunotherapeutic strategies in HCC management.
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Affiliation(s)
- Yuanxun Yue
- Department of Interventional and Pain, Beijing Luhe HospitalCapital Medical UniversityBeijingChina
| | - Zhizhong Ren
- Hepatobiliary Interventional DepartmentBeijing Tsinghua Chang Gung Hospital Affiliated to Tsinghua UniversityBeijingChina
| | - Yaqin Wang
- Hepatobiliary Interventional DepartmentBeijing Tsinghua Chang Gung Hospital Affiliated to Tsinghua UniversityBeijingChina
| | - Ying Liu
- Hepatobiliary Interventional DepartmentBeijing Tsinghua Chang Gung Hospital Affiliated to Tsinghua UniversityBeijingChina
| | - Xiaowei Yang
- Hepatobiliary Interventional DepartmentBeijing Tsinghua Chang Gung Hospital Affiliated to Tsinghua UniversityBeijingChina
| | - Tianxiao Wang
- Hepatobiliary Interventional DepartmentBeijing Tsinghua Chang Gung Hospital Affiliated to Tsinghua UniversityBeijingChina
| | | | - He Zhou
- Shanghai Dengding BioAI Co.ShanghaiChina
| | | | - Sujun Li
- Translational Medicine Institute of Jiangxi, The First Affiliated Hospital of Nanchang UniversityNanchangChina
- JiangXi Key Laboratory of Transfusion MedicineNanchangChina
| | - Yuewei Zhang
- Hepatobiliary Interventional DepartmentBeijing Tsinghua Chang Gung Hospital Affiliated to Tsinghua UniversityBeijingChina
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Ouyang J, Yang Y, Zhou Y, Chang X, Wang Z, Li Q, Tang Y, Cai J, Zhou J, Huang Z, Zhao H. Adjuvant camrelizumab plus apatinib in resected hepatocellular carcinoma with microvascular invasion: a multi-center real world study. Hepatobiliary Surg Nutr 2024; 13:616-631. [PMID: 39175713 PMCID: PMC11336524 DOI: 10.21037/hbsn-23-363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 11/06/2023] [Indexed: 08/24/2024]
Abstract
Background Hepatocellular carcinoma (HCC) treatment currently lacks adjuvant therapy with a high level of supporting evidence to reduce recurrence after hepatectomy. This study aimed to assess the safety and efficacy of camrelizumab plus apatinib in the adjuvant therapy of patients with HCC with microvascular invasion (MVI). Methods Data were retrospectively collected on consecutive patients with HCC who underwent radical resection and were diagnosed with MVI-positive tumors between October 2019 and June 2022 at four centers. The association between adjuvant therapy and prognosis [recurrence-free survival (RFS), overall survival (OS)] was evaluated by propensity score matching (PSM), the log-rank test, Cox regression analysis, and subgroup analysis. Furthermore, grade 3 or 4 treatment-related adverse events (TRAEs) of adjuvant therapy were reported. Results Among the 111 patients in the adjuvant therapy group and 276 patients in the observation group at enrolment, there were 99 and 172 in the adjuvant therapy and observation groups after PSM, respectively. RFS was better in the adjuvant therapy group [hazard ratio (HR) 0.52; 95% confidence interval (CI): 0.39 to 0.69; P<0.001], whereas OS was not (HR 0.62; 95% CI: 0.39 to 0.99; P=0.079). These results were confirmed after PSM. Subgroup analyses were generally consistent in favour of adjuvant camrelizumab plus apatinib with better RFS. Grade 3 or 4 TRAEs accounted for 20.7% during adjuvant therapy; the most common TRAEs included hypertension and proteinuria. Conclusions Postoperative adjuvant camrelizumab plus apatinib significantly improved the RFS benefits with acceptable toxicities in patients with HCC with MVI.
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Affiliation(s)
- Jingzhong Ouyang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Key Laboratory of Gene Editing Screening and Research and Development (R&D) of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yi Yang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Key Laboratory of Gene Editing Screening and Research and Development (R&D) of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yanzhao Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Xu Chang
- Department of Interventional Therapy II, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Zhengzheng Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Qingjun Li
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Yu Tang
- Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianqiang Cai
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Key Laboratory of Gene Editing Screening and Research and Development (R&D) of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jinxue Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Zhen Huang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Key Laboratory of Gene Editing Screening and Research and Development (R&D) of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hong Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Key Laboratory of Gene Editing Screening and Research and Development (R&D) of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Li CC, Liu M, Lee HP, Wu W, Ma L. Heterogeneity in Liver Cancer Immune Microenvironment: Emerging Single-Cell and Spatial Perspectives. Semin Liver Dis 2024; 44:133-146. [PMID: 38788780 DOI: 10.1055/s-0044-1787152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/26/2024]
Abstract
Primary liver cancer is a solid malignancy with a high mortality rate. The success of immunotherapy has shown great promise in improving patient care and highlights a crucial need to understand the complexity of the liver tumor immune microenvironment (TIME). Recent advances in single-cell and spatial omics technologies, coupled with the development of systems biology approaches, are rapidly transforming the landscape of tumor immunology. Here we review the cellular landscape of liver TIME from single-cell and spatial perspectives. We also discuss the cellular interaction networks within the tumor cell community in regulating immune responses. We further highlight the challenges and opportunities with implications for biomarker discovery, patient stratification, and combination immunotherapies.
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Affiliation(s)
- Caiyi Cherry Li
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Meng Liu
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Hsin-Pei Lee
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Wenqi Wu
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Lichun Ma
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
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Wei H, Dong C, Li X. Treatment Options for Hepatocellular Carcinoma Using Immunotherapy: Present and Future. J Clin Transl Hepatol 2024; 12:389-405. [PMID: 38638377 PMCID: PMC11022065 DOI: 10.14218/jcth.2023.00462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 01/22/2024] [Accepted: 01/25/2024] [Indexed: 04/20/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a common cancer, and the body's immune responses greatly affect its progression and the prognosis of patients. Immunological suppression and the maintenance of self-tolerance in the tumor microenvironment are essential responses, and these form part of the theoretical foundations of immunotherapy. In this review, we first discuss the tumor microenvironment of HCC, describe immunosuppression in HCC, and review the major biomarkers used to track HCC progression and response to treatment. We then examine antibody-based therapies, with a focus on immune checkpoint inhibitors (ICIs), monoclonal antibodies that target key proteins in the immune response (programmed cell death protein 1, anti-cytotoxic T-lymphocyte associated protein 4, and programmed death-ligand 1) which have transformed the treatment of HCC and other cancers. ICIs may be used alone or in conjunction with various targeted therapies for patients with advanced HCC who are receiving first-line treatments or subsequent treatments. We also discuss the use of different cellular immunotherapies, including T cell receptor (TCR) T cell therapy and chimeric antigen receptor (CAR) T cell therapy. We then review the use of HCC vaccines, adjuvant immunotherapy, and oncolytic virotherapy, and describe the goals of future research in the development of treatments for HCC.
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Affiliation(s)
- Hongbin Wei
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Chunlu Dong
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, Gansu, China
- Cancer Prevention and Treatment Center of Lanzhou University School of Medicine, Lanzhou, Gansu, China
- Hepatopancreatobiliary Surgery Institute of Gansu Province, Lanzhou, Gansu, China
- Clinical Research Center for General Surgery of Gansu Province, Lanzhou, Gansu, China
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Hazari Y, Chevet E, Bailly-Maitre B, Hetz C. ER stress signaling at the interphase between MASH and HCC. Hepatology 2024:01515467-990000000-00844. [PMID: 38626349 DOI: 10.1097/hep.0000000000000893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 03/28/2024] [Indexed: 04/18/2024]
Abstract
HCC is the most frequent primary liver cancer with an extremely poor prognosis and often develops on preset of chronic liver diseases. Major risk factors for HCC include metabolic dysfunction-associated steatohepatitis, a complex multifactorial condition associated with abnormal endoplasmic reticulum (ER) proteostasis. To cope with ER stress, the unfolded protein response engages adaptive reactions to restore the secretory capacity of the cell. Recent advances revealed that ER stress signaling plays a critical role in HCC progression. Here, we propose that chronic ER stress is a common transversal factor contributing to the transition from liver disease (risk factor) to HCC. Interventional strategies to target the unfolded protein response in HCC, such as cancer therapy, are also discussed.
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Affiliation(s)
- Younis Hazari
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
- Faculty of Medicine, Biomedical Neuroscience Institute (BNI), University of Chile, Santiago, Chile
- Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, Chile
- Department of Biotechnology, University of Kashmir, Srinagar, India
| | - Eric Chevet
- Inserm U1242, University of Rennes, Rennes, France
- Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France
| | - Béatrice Bailly-Maitre
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1065, Université Côte d'Azur (UCA), Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Team "Metainflammation and Hematometabolism", Metabolism Department, France
- Université Côte d'Azur, INSERM, U1065, C3M, 06200 Nice, France
| | - Claudio Hetz
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
- Faculty of Medicine, Biomedical Neuroscience Institute (BNI), University of Chile, Santiago, Chile
- Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, Chile
- Buck Institute for Research on Aging, Novato, California, USA
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Xing H, Li X. Engineered Nanomaterials for Tumor Immune Microenvironment Modulation in Cancer Immunotherapy. Chemistry 2024:e202400425. [PMID: 38576219 DOI: 10.1002/chem.202400425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 03/28/2024] [Accepted: 04/02/2024] [Indexed: 04/06/2024]
Abstract
Tumor immunotherapy, represented by immune checkpoint blocking and chimeric antigen receptor (CAR) T cell therapy, has achieved promising results in clinical applications. However, it faces challenges that hinder its further development, such as limited response rates and poor tumor permeability. The efficiency of tumor immunotherapy is also closely linked to the structure and function of the immune microenvironment where the tumor resides. Recently, nanoparticle-based tumor immune microenvironment (TIME) modulation strategies have attracted a great deal of attention in cancer immunotherapy. This is primarily due to the distinctive physical characteristics of nanoparticles, which enable them to effectively infiltrate the TIME and selectively modulate its key constituents. This paper reviews recent advances in nanoparticle engineering to improve anti-cancer immunotherapy. Emerging nanoparticle-based approaches for modulating immune cells, tumor stroma, cytokines and immune checkpoints are discussed, aiming to overcome current challenges in the clinic. In addition, integrating immunotherapy with various treatment modalities such as chemotherapy and photodynamic therapy can be facilitated through the utilization of nanoparticles, thereby enhancing the efficacy of cancer treatment. The future challenges and opportunities of using nanomaterials to reeducate the suppressive immune microenvironment of tumors are also discussed, with the aim of anticipating further advancements in this growing field.
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Affiliation(s)
- Hao Xing
- Department of General Surgery, Naval Medical Center, Naval Medical University, 200052, Shanghai, China
- The First Affiliated Hospital of Naval Medical University, 200433, Shanghai, China
| | - Xiaomin Li
- Department of Chemistry, Laboratory of Advanced Materials, College of Chemistry and Materials, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, State Key Laboratory of Molecular Engineering of Polymers, Collaborative Innovation Center of Chemistry for Energy Materials (2011-iChEM), Fudan University, 200438, Shanghai, China
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Li Y, Shi J, Liu Z, Lin Y, Xie A, Sun W, Liu J, Liang J. Regulation of the migration of colorectal cancer stem cells via the TLR4/MyD88 signaling pathway by the novel surface marker CD14 following LPS stimulation. Oncol Lett 2024; 27:60. [PMID: 38192670 PMCID: PMC10773188 DOI: 10.3892/ol.2023.14194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 11/24/2023] [Indexed: 01/10/2024] Open
Abstract
Cell surface markers are most widely used in the study of cancer stem cells (CSCs). However, cell surface markers that are safely and stably expressed in CSCs have yet to be identified. Colonic CSCs express leukocyte CD14. CD14 binding to the ligand lipopolysaccharide (LPS) is involved in the inflammatory response via the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88) signaling pathway. TLR4 and MyD88 have been reported to promote the proliferation, metastasis and tumorigenicity of colon cancer cells, which is consistent with the characteristics of CSCs. In the present study, the proposed experimental method to detect cell proliferation, metastasis and tumorigenesis was used to confirm that, under LPS stimulation, CD14 promoted the proliferation, migration and tumorigenesis of colonic CSCs via the TLR4/MyD88 signaling pathway. Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine assays were used to assess the proliferation and migration of the cells. Colony formation and nude mouse xenograft assays were used to assess the capacity of cells to form tumors. Using western blotting and reverse transcription-quantitative PCR, the mRNA and protein levels of CD14, TLR4 and MyD88 were examined. It was confirmed that CD14 promoted the proliferation, metastasis and tumorigenesis of colon CSCs in response to LPS stimulation via the TLR4/MyD88 signaling pathway, and CD14+ colon cancer cells were successfully isolated and sorted. According to the results of proliferation assay, it was determined that CD14 regulated the LPS-induced proliferation of colon CSCs. CD14, TLR4 and MyD88 protein and mRNA expression was upregulated in colon CSCs in response to LPS stimulation. This indicates a potential novel target for colon CSC-related studies.
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Affiliation(s)
- Yufei Li
- Morphology Laboratory, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Jiayi Shi
- School of Life Sciences, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Zhixin Liu
- Morphology Laboratory, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Yonggang Lin
- Department of Extracorporeal Circulation, Mudanjiang Cardiovascular Disease Hospital, Mudanjiang, Heilongjiang 157011, P.R. China
| | - An Xie
- Morphology Laboratory, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Wenxiu Sun
- Morphology Laboratory, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Jiaqi Liu
- Morphology Laboratory, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Jun Liang
- Morphology Laboratory, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
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Zhao Y, Yang T, Ouyang Y, Rao W, Liu K, Zheng J, Lv F, Shi Y, Wang F, Liu D, Qiao L, Xia Z, Zhang Y, Chen D, Wang W. Radiofrequency ablation plays double role in immunosuppression and activation of PBMCs in recurrent hepatocellular carcinoma. Front Immunol 2024; 15:1339213. [PMID: 38348038 PMCID: PMC10859425 DOI: 10.3389/fimmu.2024.1339213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 01/11/2024] [Indexed: 02/15/2024] Open
Abstract
Background Radiofrequency ablation (RFA) is the primary curative treatment for hepatocellular carcinoma (HCC) patients who are not eligible for surgery. However, the effects of RFA on the global tumor immune response remain unclear. Method In this study, we examined the phenotypic and functional changes in peripheral blood mononuclear cells (PBMCs) from recurrent HCC patients who had undergone two RFA treatments using mass cytometry and high-throughput mRNA assays. Results We observed significant increase in monocytes and decrease in T cell subpopulations three days after the first RFA treatment and three days after the second RFA treatment. The down-regulation of GZMB, GZMH, GZMK, and CD8A, which are involved in the cytotoxic function of T cells, was observed following RFA. Furthermore, the population of CD8 effector and memory T cells (CD8 Teff and CD8 Tem) significantly decreased after RFA. The expression of CD5 and CD161 in various T cell subpopulations also showed significant reductions. Additionally, elevated secretion of VEGF was observed in monocytes, B cells, regulatory T cells (Tregs), and CD4 naive T cells. Conclusion In recurrent HCC patients, serum components derived from radiofrequency therapy can enhance the antigen-presenting capacity of monocytes. However, they also inhibit the anti-cancer immune response by reducing the population of CD8 effector and memory T cells and suppressing the activation of T cells, as well as down-regulating the expression of CD161 and CD5 in various T cell subpopulations. These tumor-derived components also contribute to an immunosuppressive microenvironment by promoting the secretion of VEGF in monocytes, Tregs, B cells, and CD4 naive T cells.
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Affiliation(s)
- Yang Zhao
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- The Affiliated Hospital of Qingdao University, Organ Transplantation Center, Qingdao, Shandong, China
| | - Tongwang Yang
- Beijing YouAn Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing, China
- Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer, Beijing, China
| | - Yabo Ouyang
- Beijing YouAn Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing, China
- Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer, Beijing, China
| | - Wei Rao
- The Affiliated Hospital of Qingdao University, Organ Transplantation Center, Qingdao, Shandong, China
| | - Kai Liu
- Beijing YouAn Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing, China
- Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer, Beijing, China
| | - Jiasheng Zheng
- Beijing YouAn Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing, China
| | - Fudong Lv
- Beijing YouAn Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing, China
| | - Ying Shi
- Beijing YouAn Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing, China
- Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer, Beijing, China
| | - Feng Wang
- The Affiliated Hospital of Qingdao University, Organ Transplantation Center, Qingdao, Shandong, China
| | - Dongjie Liu
- Beijing YouAn Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing, China
- Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer, Beijing, China
| | - Luxin Qiao
- Beijing YouAn Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing, China
- Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer, Beijing, China
| | - Zhenying Xia
- The Affiliated Hospital of Qingdao University, Organ Transplantation Center, Qingdao, Shandong, China
| | - Yushi Zhang
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Dexi Chen
- The Affiliated Hospital of Qingdao University, Organ Transplantation Center, Qingdao, Shandong, China
- Beijing YouAn Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing, China
- Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer, Beijing, China
| | - Wenjing Wang
- Beijing YouAn Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing, China
- Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer, Beijing, China
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11
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Gu XY, Huo JL, Yu ZY, Jiang JC, Xu YX, Zhao LJ. Immunotherapy in hepatocellular carcinoma: an overview of immune checkpoint inhibitors, drug resistance, and adverse effects. ONCOLOGIE 2024; 26:9-25. [DOI: 10.1515/oncologie-2023-0412] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Abstract
Hepatocellular carcinoma (HCC) is a concerning liver cancer with rising incidence and mortality rates worldwide. The effectiveness of traditional therapies in managing advanced HCC is limited, necessitating the development of new therapeutic strategies. Immune checkpoint inhibitors (ICIs) have emerged as a promising strategy for HCC management. By preventing tumor cells from evading immune surveillance through immunological checkpoints, ICIs can restore the immune system’s ability to target and eliminate tumors. While ICIs show promise in enhancing the immune response against malignancies, challenges such as drug resistance and adverse reactions hinder their efficacy. To address these challenges, developing individualized ICI treatment strategies is critical. Combining targeted therapy and immunotherapy holds the potential for comprehensive therapeutic effects. Additionally, biomarker-based individualized ICI treatment strategies offer promise in predicting treatment response and guiding personalized patient care. Future research should explore emerging ICI treatment methods to optimize HCC immunotherapy. This review provides an overview of ICIs as a new treatment for HCC, demonstrating some success in promoting the tumor immune response. However, drug resistance and adverse reactions remain important considerations that must be addressed. As tailored treatment plans evolve, the prospect of immunotherapy for HCC is expected to grow, offering new opportunities for improved patient outcomes.
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Affiliation(s)
- Xuan-Yu Gu
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
| | - Jin-Long Huo
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
| | - Zhi-Yong Yu
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
| | - Ji-Chang Jiang
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
| | - Ya-Xuan Xu
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
| | - Li-Jin Zhao
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
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12
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Addala V, Newell F, Pearson JV, Redwood A, Robinson BW, Creaney J, Waddell N. Computational immunogenomic approaches to predict response to cancer immunotherapies. Nat Rev Clin Oncol 2024; 21:28-46. [PMID: 37907723 DOI: 10.1038/s41571-023-00830-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/03/2023] [Indexed: 11/02/2023]
Abstract
Cancer immunogenomics is an emerging field that bridges genomics and immunology. The establishment of large-scale genomic collaborative efforts along with the development of new single-cell transcriptomic techniques and multi-omics approaches have enabled characterization of the mutational and transcriptional profiles of many cancer types and helped to identify clinically actionable alterations as well as predictive and prognostic biomarkers. Researchers have developed computational approaches and machine learning algorithms to accurately obtain clinically useful information from genomic and transcriptomic sequencing data from bulk tissue or single cells and explore tumours and their microenvironment. The rapid growth in sequencing and computational approaches has resulted in the unmet need to understand their true potential and limitations in enabling improvements in the management of patients with cancer who are receiving immunotherapies. In this Review, we describe the computational approaches currently available to analyse bulk tissue and single-cell sequencing data from cancer, stromal and immune cells, as well as how best to select the most appropriate tool to address various clinical questions and, ultimately, improve patient outcomes.
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Affiliation(s)
- Venkateswar Addala
- Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
| | - Felicity Newell
- Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - John V Pearson
- Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Alec Redwood
- National Centre for Asbestos Related Diseases, University of Western Australia, Perth, Western Australia, Australia
- Institute of Respiratory Health, Perth, Western Australia, Australia
- School of Biomedical Science, University of Western Australia, Perth, Western Australia, Australia
| | - Bruce W Robinson
- National Centre for Asbestos Related Diseases, University of Western Australia, Perth, Western Australia, Australia
- Institute of Respiratory Health, Perth, Western Australia, Australia
- Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
- Medical School, University of Western Australia, Perth, Western Australia, Australia
| | - Jenette Creaney
- National Centre for Asbestos Related Diseases, University of Western Australia, Perth, Western Australia, Australia
- Institute of Respiratory Health, Perth, Western Australia, Australia
- School of Biomedical Science, University of Western Australia, Perth, Western Australia, Australia
- Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
| | - Nicola Waddell
- Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
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13
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Tang Y, Shu Z, Zhu M, Li S, Ling Y, Fu Y, Hu Z, Wang J, Yang Z, Liao J, Xu L, Yu M, Peng Z. Size-Tunable Nanoregulator-Based Radiofrequency Ablation Suppresses MDSCs and Their Compensatory Immune Evasion in Hepatocellular Carcinoma. Adv Healthc Mater 2023; 12:e2302013. [PMID: 37665720 DOI: 10.1002/adhm.202302013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 09/01/2023] [Indexed: 09/06/2023]
Abstract
Radiofrequency ablation (RFA) is a widely used therapy for hepatocellular carcinoma (HCC). However, in cases of insufficient RFA (iRFA), nonlethal temperatures in the transition zone increase the risk of postoperative relapse. The pathological analysis of HCC tissues shows that iRFA-induced upregulation of myeloid-derived suppressor cells (MDSCs) in residual tumors is critical for postoperative recurrence. Furthermore, this study demonstrates, for the first time, that combining MDSCs suppression strategy during iRFA can unexpectedly lead to a compensatory increase in PD-L1 expression on the residual MDSCs, attributed to relapse due to immune evasion. To address this issue, a novel size-tunable hybrid nano-microliposome is designed to co-deliver MDSCs inhibitors (IPI549) and αPDL1 antibodies (LPIP) for multipathway activation of immune responses. The LPIP is triggered to release immune regulators by the mild heat in the transition zone of iRFA, selectively inhibiting MDSCs and blocking the compensatory upregulation of PD-L1 on surviving MDSCs. The combined strategy of LPIP + iRFA effectively ablates the primary tumor by activating immune responses in the transition zone while suppressing the compensatory immune evasion of surviving MDSCs. This approach avoids the relapse of the residual tumor in a post-iRFA incomplete ablation model and appears to be a promising strategy in RFA for the eradication of HCC.
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Affiliation(s)
- Yuhao Tang
- Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P. R. China
- Department of Liver Surgery, The Sun Yat-sen University Cancer Center, Guangzhou, 510080, P. R. China
| | - Zhilin Shu
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism and Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Meiyan Zhu
- Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P. R. China
| | - Shuping Li
- Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P. R. China
| | - Yunyan Ling
- Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P. R. China
| | - Yizhen Fu
- Department of Liver Surgery, The Sun Yat-sen University Cancer Center, Guangzhou, 510080, P. R. China
| | - Zili Hu
- Department of Liver Surgery, The Sun Yat-sen University Cancer Center, Guangzhou, 510080, P. R. China
| | - Jiongliang Wang
- Department of Liver Surgery, The Sun Yat-sen University Cancer Center, Guangzhou, 510080, P. R. China
| | - Zhenyun Yang
- Department of Liver Surgery, The Sun Yat-sen University Cancer Center, Guangzhou, 510080, P. R. China
| | - Junbin Liao
- Department of Liver Surgery, Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P. R. China
| | - Li Xu
- Department of Liver Surgery, The Sun Yat-sen University Cancer Center, Guangzhou, 510080, P. R. China
| | - Meng Yu
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism and Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
- Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Zhenwei Peng
- Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P. R. China
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P. R. China
- Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P. R. China
- Cancer Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P. R. China
- Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P. R. China
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14
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Yi M, Li T, Niu M, Mei Q, Zhao B, Chu Q, Dai Z, Wu K. Exploiting innate immunity for cancer immunotherapy. Mol Cancer 2023; 22:187. [PMID: 38008741 PMCID: PMC10680233 DOI: 10.1186/s12943-023-01885-w] [Citation(s) in RCA: 72] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 10/23/2023] [Indexed: 11/28/2023] Open
Abstract
Immunotherapies have revolutionized the treatment paradigms of various types of cancers. However, most of these immunomodulatory strategies focus on harnessing adaptive immunity, mainly by inhibiting immunosuppressive signaling with immune checkpoint blockade, or enhancing immunostimulatory signaling with bispecific T cell engager and chimeric antigen receptor (CAR)-T cell. Although these agents have already achieved great success, only a tiny percentage of patients could benefit from immunotherapies. Actually, immunotherapy efficacy is determined by multiple components in the tumor microenvironment beyond adaptive immunity. Cells from the innate arm of the immune system, such as macrophages, dendritic cells, myeloid-derived suppressor cells, neutrophils, natural killer cells, and unconventional T cells, also participate in cancer immune evasion and surveillance. Considering that the innate arm is the cornerstone of the antitumor immune response, utilizing innate immunity provides potential therapeutic options for cancer control. Up to now, strategies exploiting innate immunity, such as agonists of stimulator of interferon genes, CAR-macrophage or -natural killer cell therapies, metabolic regulators, and novel immune checkpoint blockade, have exhibited potent antitumor activities in preclinical and clinical studies. Here, we summarize the latest insights into the potential roles of innate cells in antitumor immunity and discuss the advances in innate arm-targeted therapeutic strategies.
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Affiliation(s)
- Ming Yi
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People's Republic of China
- Department of Breast Surgery, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, 310000, People's Republic of China
| | - Tianye Li
- Department of Gynecology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310000, People's Republic of China
| | - Mengke Niu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Qi Mei
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People's Republic of China
| | - Bin Zhao
- Department of Breast Surgery, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, 310000, People's Republic of China
| | - Qian Chu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China.
| | - Zhijun Dai
- Department of Breast Surgery, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, 310000, People's Republic of China.
| | - Kongming Wu
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People's Republic of China.
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China.
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15
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Tamai Y, Fujiwara N, Tanaka T, Mizuno S, Nakagawa H. Combination Therapy of Immune Checkpoint Inhibitors with Locoregional Therapy for Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:5072. [PMID: 37894439 PMCID: PMC10605879 DOI: 10.3390/cancers15205072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 10/17/2023] [Accepted: 10/18/2023] [Indexed: 10/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is estimated to be the fourth leading cause of cancer-related deaths globally, and its overall prognosis is dismal because most cases are diagnosed at a late stage and are unamenable to curative treatment. The emergence of immune checkpoint inhibitors (ICIs) has dramatically improved the therapeutic efficacy for advanced hepatocellular carcinoma; however, their response rates remain unsatisfactory, partly because >50% of HCC exhibit an ICI-nonresponsive tumor microenvironment characterized by a paucity of cytotoxic T cells (immune-cold), as well as difficulty in their infiltration into tumor sites (immune excluded). To overcome this limitation, combination therapies with locoregional therapies, including ablation, transarterial embolization, and radiotherapy, which are usually used for early stage HCCs, have been actively explored to enhance ICI efficacy by promoting the release of tumor-associated antigens and cytokines, and eventually accelerating the so-called cancer-immunity cycle. Various combination therapies have been investigated in early- to late-phase clinical trials, and some have shown promising results. This comprehensive article provides an overview of the immune landscape for HCC to understand ICI efficacy and its limitations and, subsequently, reviews the status of combinatorial therapies of ICIs with locoregional therapy for HCC.
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Affiliation(s)
- Yasuyuki Tamai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu 514-8507, Japan; (Y.T.); (T.T.); (H.N.)
| | - Naoto Fujiwara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu 514-8507, Japan; (Y.T.); (T.T.); (H.N.)
| | - Takamitsu Tanaka
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu 514-8507, Japan; (Y.T.); (T.T.); (H.N.)
| | - Shugo Mizuno
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Graduate School of Medicine, Mie University, Tsu 514-8507, Japan;
| | - Hayato Nakagawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu 514-8507, Japan; (Y.T.); (T.T.); (H.N.)
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16
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Lee JY, Kim S, Sohn HJ, Kim CH, Kim TG, Lee HS. Local Myeloid-Derived Suppressor Cells Impair Progression of Experimental Autoimmune Uveitis by Alleviating Oxidative Stress and Inflammation. Invest Ophthalmol Vis Sci 2023; 64:39. [PMID: 37878302 PMCID: PMC10615146 DOI: 10.1167/iovs.64.13.39] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 10/06/2023] [Indexed: 10/26/2023] Open
Abstract
Purpose To evaluate the immune regulatory effect of human cord blood myeloid-derived suppressor cells (MDSCs) in experimental autoimmune uveitis (EAU) models. Methods MDSCs (1 × 106) or PBS were injected into established C57BL/6 EAU mice via the subconjunctival route on days 0 and 7. The severity of intraocular inflammation was evaluated for up to 3 weeks. Tissue injury and inflammation were analyzed using immunolabelled staining, real-time PCR, and ELISA. In addition, immune cells in draining lymph nodes (LNs) were quantified using flow cytometry. Results After 21 days, the clinical scores and histopathological grades of EAU were lower in the MDSCs group compared with the PBS group. Local administration of MDSCs suppressed the oxidative stress and the expression of TNF-α and IL-1β in the retinal tissues. In addition, it inhibited the activation of pathogenic T helper 1 (Th1) and Th17 cells in draining LNs. MDSCs increased the frequency of CD25+ Foxp3+ regulatory T cells and the mRNA expression of IL-10, as an immune modulator. Conclusions MDSCs suppressed inflammation and oxidative stress in the retina and inhibited pathogenic T cells in the LNs in EAU. Therefore, ocular administration of MDSCs has therapeutic potential for uveitis.
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Affiliation(s)
- Jae-Young Lee
- Department of Ophthalmology, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sueon Kim
- ViGenCell Inc., Seoul, Republic of Korea
| | | | | | - Tai-Gyu Kim
- ViGenCell Inc., Seoul, Republic of Korea
- Catholic Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyun Soo Lee
- Department of Ophthalmology, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, United States
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17
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Ozbay Kurt FG, Lasser S, Arkhypov I, Utikal J, Umansky V. Enhancing immunotherapy response in melanoma: myeloid-derived suppressor cells as a therapeutic target. J Clin Invest 2023; 133:e170762. [PMID: 37395271 DOI: 10.1172/jci170762] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/04/2023] Open
Abstract
Despite the remarkable success of immune checkpoint inhibitors (ICIs) in melanoma treatment, resistance to them remains a substantial clinical challenge. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of myeloid cells that can suppress antitumor immune responses mediated by T and natural killer cells and promote tumor growth. They are major contributors to ICI resistance and play a crucial role in creating an immunosuppressive tumor microenvironment. Therefore, targeting MDSCs is considered a promising strategy to improve the therapeutic efficacy of ICIs. This Review describes the mechanism of MDSC-mediated immune suppression, preclinical and clinical studies on MDSC targeting, and potential strategies for inhibiting MDSC functions to improve melanoma immunotherapy.
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Affiliation(s)
- Feyza Gul Ozbay Kurt
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
| | - Samantha Lasser
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
| | - Ihor Arkhypov
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
| | - Jochen Utikal
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
| | - Viktor Umansky
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
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18
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Khan F, Jones K, Lyon P. Immune checkpoint inhibition: a future guided by radiology. Br J Radiol 2023; 96:20220565. [PMID: 36752570 PMCID: PMC10321249 DOI: 10.1259/bjr.20220565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 01/04/2023] [Accepted: 01/29/2023] [Indexed: 02/09/2023] Open
Abstract
The limitation of the function of antitumour immune cells is a common hallmark of cancers that enables their survival. As such, the potential of immune checkpoint inhibition (ICI) acts as a paradigm shift in the treatment of a range of cancers but has not yet been fully capitalised. Combining minimally and non-invasive locoregional therapies offered by radiologists with ICI is now an active field of research with the aim of furthering therapeutic capabilities in medical oncology. In parallel to this impending advancement, the "imaging toolbox" available to radiologists is also growing, enabling more refined tumour characterisation as well as greater accuracy in evaluating responses to therapy. Options range from metabolite labelling to cellular localisation to immune checkpoint screening. It is foreseeable that these novel imaging techniques will be integrated into personalised treatment algorithms. This growth in the field must include updating the current standardised imaging criteria to ensure they are fit for purpose. Such criteria is crucial to both appropriately guide clinical decision-making regarding next steps of treatment, but also provide reliable prognosis. Quantitative approaches to these novel imaging techniques are also already being investigated to further optimise personalised therapeutic decision-making. The therapeutic potential of specific ICIs and locoregional therapies could be determined before administration thus limiting unnecessary side-effects whilst maintaining efficacy. Several radiological aspects of oncological care are advancing simultaneously. Therefore, it is essential that each development is assessed for clinical use and optimised to ensure the best treatment decisions are being offered to the patient. In this review, we discuss state of the art advances in novel functional imaging techniques in the field of immuno-oncology both pre-clinically and clinically.
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Affiliation(s)
- Faraaz Khan
- Foundation Doctor, Buckinghamshire Hospitals NHS Trust, Amersham, Buckinghamshire, United Kingdom
| | - Keaton Jones
- Academic Clinical Lecturer Nuffield Department of Surgical Sciences University of Oxford, Wellington Square, Oxford, United Kingdom
| | - Paul Lyon
- Consultant Radiologist, Department of Radiology, Oxford University Hospitals, Headington, Oxford, United Kingdom
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19
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Chen X, Li Y, Xia H, Chen YH. Monocytes in Tumorigenesis and Tumor Immunotherapy. Cells 2023; 12:1673. [PMID: 37443711 PMCID: PMC10340267 DOI: 10.3390/cells12131673] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 06/07/2023] [Accepted: 06/08/2023] [Indexed: 07/15/2023] Open
Abstract
Monocytes are highly plastic innate immune cells that display significant heterogeneity during homeostasis, inflammation, and tumorigenesis. Tumor-induced systemic and local microenvironmental changes influence the phenotype, differentiation, and distribution of monocytes. Meanwhile, monocytes and their related cell subsets perform an important regulatory role in the development of many cancers by affecting tumor growth or metastasis. Thanks to recent advances in single-cell technologies, the nature of monocyte heterogeneity and subset-specific functions have become increasingly clear, making it possible to systematically analyze subset-specific roles of monocytes in tumorigenesis. In this review, we discuss recent discoveries related to monocytes and tumorigenesis, and new strategies for tumor biomarker identification and anti-tumor immunotherapy.
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Affiliation(s)
| | | | - Houjun Xia
- Center for Cancer Immunology, Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen 518000, China; (X.C.); (Y.L.)
| | - Youhai H. Chen
- Center for Cancer Immunology, Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen 518000, China; (X.C.); (Y.L.)
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20
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Chen S, Shen B, Wu Y, Shen L, Qi H, Cao F, Huang T, Tan H, Wen C, Fan W. The relationship between the efficacy of thermal ablation and inflammatory response and immune status in early hepatocellular carcinoma and the progress of postoperative adjuvant therapy. Int Immunopharmacol 2023; 119:110228. [PMID: 37121111 DOI: 10.1016/j.intimp.2023.110228] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 04/10/2023] [Accepted: 04/20/2023] [Indexed: 05/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous disease. Thermal ablation has the advantages of being equivalent to surgical resection, minimally invasive, low cost and significantly reducing hospital stay. Therefore, it is recommended as one of the first-line radical treatment for early HCC. However, with the deepening of research on early HCC, more and more studies have found that not all patients with early HCC can obtain similar efficacy after radical thermal ablation, which may be related to the heterogeneity of HCC. Previous studies have shown that inflammation and immunity play an extremely important role in the prognostic heterogeneity of patients with HCC. Therefore, the inflammatory response and immune status of patients may be closely related to the efficacy of early HCC after curative thermal ablation. This article elaborates the mechanism of high inflammatory response and poor immune status in the poor prognosis after radical thermal ablation of early HCC, and clarifies the population who may benefit from adjuvant therapy after radical thermal ablation in patients with early HCC, which provides a new idea for the precise adjuvant treatment after radical ablation of early HCC in the future.
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Affiliation(s)
- Shuanggang Chen
- Department of Oncology, Yuebei People's Hospital, Shantou University Medical College, Shaoguan 512025, Guangdong, People's Republic of China; Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China.
| | - Binyan Shen
- Department of Nursing, Medical College of Shaoguan University, Shaoguan 512026, People's Republic of China
| | - Ying Wu
- Department of Interventional Therapy, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China
| | - Lujun Shen
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, People's Republic of China
| | - Han Qi
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, People's Republic of China
| | - Fei Cao
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, People's Republic of China
| | - Tao Huang
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, People's Republic of China
| | - Hongtong Tan
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, People's Republic of China
| | - Chunyong Wen
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, People's Republic of China
| | - Weijun Fan
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, People's Republic of China.
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21
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Yang SF, Weng MT, Liang JD, Chiou LL, Hsu YC, Lee YT, Liu SY, Wu MC, Chou HC, Wang LF, Yu SH, Lee HS, Sheu JC. Neoantigen vaccination augments antitumor effects of anti-PD-1 on mouse hepatocellular carcinoma. Cancer Lett 2023; 563:216192. [PMID: 37088327 DOI: 10.1016/j.canlet.2023.216192] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 03/15/2023] [Accepted: 04/18/2023] [Indexed: 04/25/2023]
Abstract
Immune checkpoint inhibitors are groundbreaking resources for cancer therapy. However, only a few patients with hepatocellular carcinoma (HCC) have shown positive responses to anti-PD-1 therapy. Neoantigens are sequence-altered proteins resulting from somatic mutations in cancer. This study identified the neoantigens of Hep-55.1C and Dt81 Hepa1-6 HCCs by comparing their whole exome sequences with those of a normal C57BL/6 mouse liver. Immunogenic long peptides were pooled as peptide vaccines. The vaccination elicited tumor-reactive immune responses in C57BL/6 mice, as demonstrated by IFN-γ ELISPOT and an in vitro killing assay of splenocytes. In the treatment of three mouse HCC models, combined neoantigen vaccination and anti-PD-1 resulted in more significant tumor regression than monotherapies. Flow cytometry of the tumor-infiltrating lymphocytes showed decreased Treg cells and monocytic myeloid-derived suppressor cells, increased CD8+ T cells, enhanced granzyme B expression, and reduced exhaustion-related markers PD-1 and Lag-3 on CD8+ T cells in the combination group. These findings provide a strong rationale for conducting clinical studies of using neoantigen vaccination in combination with anti-PD-1 to treat patients with HCC.
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Affiliation(s)
- Shih-Feng Yang
- Institute of Biotechnology, National Taiwan University, Taipei, Taiwan.
| | - Meng-Tzu Weng
- Department of Medical Research, National Taiwan University Hospital, Hsin-Chu Branch, Hsinchu, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
| | - Ja-Der Liang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
| | - Ling-Ling Chiou
- Liver Disease Prevention & Treatment Research Foundation, Taipei, Taiwan.
| | - Yu-Chen Hsu
- Liver Disease Prevention & Treatment Research Foundation, Taipei, Taiwan.
| | - Ying-Te Lee
- Liver Disease Prevention & Treatment Research Foundation, Taipei, Taiwan.
| | - Shin-Yun Liu
- Liver Disease Prevention & Treatment Research Foundation, Taipei, Taiwan.
| | - Meng-Chuan Wu
- Liver Disease Prevention & Treatment Research Foundation, Taipei, Taiwan.
| | - Huei-Chi Chou
- Liver Disease Prevention & Treatment Research Foundation, Taipei, Taiwan.
| | - Li-Fang Wang
- Liver Disease Prevention & Treatment Research Foundation, Taipei, Taiwan.
| | - Shu-Han Yu
- Institute of Biotechnology, National Taiwan University, Taipei, Taiwan.
| | - Hsuan-Shu Lee
- Institute of Biotechnology, National Taiwan University, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Liver Disease Prevention & Treatment Research Foundation, Taipei, Taiwan.
| | - Jin-Chuan Sheu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Liver Disease Prevention & Treatment Research Foundation, Taipei, Taiwan.
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22
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Nikoo M, Hassan ZF, Mardasi M, Rostamnezhad E, Roozbahani F, Rahimi S, Mohammadi J. Hepatocellular carcinoma (HCC) immunotherapy by anti-PD-1 monoclonal antibodies: A rapidly evolving strategy. Pathol Res Pract 2023; 247:154473. [PMID: 37207558 DOI: 10.1016/j.prp.2023.154473] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 04/16/2023] [Accepted: 04/18/2023] [Indexed: 05/21/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world, with a high relapse rate. Delayed symptom onset observed in 70-80% of patients leads to diagnosis in advanced stages commonly associated with chronic liver disease. Programmed cell death protein 1 (PD-1) blockade therapy has recently emerged as a promising therapeutic option in the clinical management of several advanced malignancies, including HCC, due to the activation of exhausted tumor-infiltrating lymphocytes and improved outcomes of T-cell function. However, many people with HCC do not respond to PD-1 blockade therapy, and the diversity of immune-related adverse events (irAEs) restricts their clinical utility. Therefore, numerous effective combinatory strategies, including combinations with anti-PD-1 antibodies and other therapeutic methods ranging from chemotherapy to targeted therapies, are evolving to improve therapeutic outcomes and evoke synergistic anti-tumor impressions in patients with advanced HCC. Unfortunately, combined therapy may have more side effects than single-agent treatment. Nonetheless, identifying appropriate predictive biomarkers can aid in managing potential immune-related adverse events by distinguishing patients who respond best to PD-1 inhibitors as single agents or in combination strategies. In the present review, we summarize the therapeutic potential of PD-1 blockade therapy for advanced HCC patients. Besides, a glimpse of the pivotal predictive biomarkers influencing a patient's response to anti-PD-1 antibodies will be provided.
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Affiliation(s)
- Marzieh Nikoo
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | | | - Mahsa Mardasi
- Biotechnology Department, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University G. C., Evin, Tehran, Iran
| | - Elmira Rostamnezhad
- Department of Molecular Genetics, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran
| | - Fatemeh Roozbahani
- Department of Microbiology and Virology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Sahel Rahimi
- Industrial and Environmental Biotechnology Department, National Institute of Genetic Engineering and Biotechnology(NIGEB), Tehran, Iran
| | - Javad Mohammadi
- Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran.
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23
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Zeng X, Liao G, Li S, Liu H, Zhao X, Li S, Lei K, Zhu S, Chen Z, Zhao Y, Ren X, Su T, Cheng ASL, Peng S, Lin S, Wang J, Chen S, Kuang M. Eliminating METTL1-mediated accumulation of PMN-MDSCs prevents hepatocellular carcinoma recurrence after radiofrequency ablation. Hepatology 2023; 77:1122-1138. [PMID: 35598182 DOI: 10.1002/hep.32585] [Citation(s) in RCA: 73] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 05/13/2022] [Accepted: 05/14/2022] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS Radiofrequency ablation (RFA) is an important curative therapy in hepatocellular carcinoma (HCC), but recurrence rate remains as high as all the other HCC therapeutic modalities. Methyltransferase 1 (METTL1), an enzyme for m 7 G tRNA modification, was reported to promote HCC development. Here, we assessed the role of METTL1 in shaping the immunosuppressive tumor microenvironment after insufficient RFA (iRFA). APPROACH AND RESULTS By immunohistochemistry and multiplex immunofluorescence (mIF) staining, we showed that METTL1 expression was enhanced in post-RFA recurrent HCC, accompanied by increased CD11b + CD15 + polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSCs) and decreased CD8 + T cells. Mechanistically, heat-mediated METTL1 upregulation enhanced TGF-β2 translation to form the immunosuppressive environment by induction of myeloid-derived suppressor cell. Liver-specific overexpression or knockdown of Mettl1 significantly affected the accumulation of PMN-MDSCs and subsequently affected CD8 + T cell infiltration. Complete RFA successfully eliminated the tumor, whereas iRFA-treated mice exhibited enhanced tumor growth and metastasis with increased PMN-MDSC accumulation and decreased CD8 + T cells compared to sham surgery. Interrupting METTL1-TGF-β2-PMN-MDSC axis by anti-Ly6G antibody, or knockdown of hepatoma-intrinsic Mettl1 or Tgfb2 , or TGF-β signaling blockade significantly mitigated tumor progression induced by iRFA and restored CD8 + T cell population. CONCLUSIONS Our study sheds light on the pivotal role of METTL1 in modulating an immunosuppressive microenvironment and demonstrated that interrupting METTL1-TGF-β2-PMN-MDSC axis could be a therapeutic strategy to restore antitumor immunity and prevent HCC recurrence after RFA treatment, meriting further clinical studies.
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Affiliation(s)
- Xuezhen Zeng
- Department of Liver Surgery , Center of Hepato-Pancreato-Biliary Surgery , The First Affiliated Hospital, Sun Yat-sen University , Guangzhou , Guangdong Province , China
- Institute of Precision Medicine , the First Affiliated Hospital , Sun Yat-sen University , Guangzhou , Guangdong Province , China
| | - Guanrui Liao
- Department of Liver Surgery , Center of Hepato-Pancreato-Biliary Surgery , The First Affiliated Hospital, Sun Yat-sen University , Guangzhou , Guangdong Province , China
| | - Shumin Li
- Department of Gastroenterology and Hepatology , The First Affiliated Hospital, Sun Yat-sen University , Guangzhou , Guangdong Province , China
| | - Haining Liu
- Department of Liver Surgery , Center of Hepato-Pancreato-Biliary Surgery , The First Affiliated Hospital, Sun Yat-sen University , Guangzhou , Guangdong Province , China
| | - Xiao Zhao
- Department of Oncology , The First Affiliated Hospital of Sun Yat-sen University , Guangzhou , Guangdong Province , China
| | - Shuang Li
- Department of Liver Surgery , Center of Hepato-Pancreato-Biliary Surgery , The First Affiliated Hospital, Sun Yat-sen University , Guangzhou , Guangdong Province , China
| | - Kai Lei
- Department of Liver Surgery , Center of Hepato-Pancreato-Biliary Surgery , The First Affiliated Hospital, Sun Yat-sen University , Guangzhou , Guangdong Province , China
| | - Shenghua Zhu
- Department of Gastroenterology and Hepatology , The First Affiliated Hospital, Sun Yat-sen University , Guangzhou , Guangdong Province , China
| | - Zhihang Chen
- Department of Liver Surgery , Center of Hepato-Pancreato-Biliary Surgery , The First Affiliated Hospital, Sun Yat-sen University , Guangzhou , Guangdong Province , China
| | - Yi Zhao
- Institute of Precision Medicine , the First Affiliated Hospital , Sun Yat-sen University , Guangzhou , Guangdong Province , China
| | - Xuxin Ren
- Institute of Precision Medicine , the First Affiliated Hospital , Sun Yat-sen University , Guangzhou , Guangdong Province , China
| | - Tianhong Su
- Institute of Precision Medicine , the First Affiliated Hospital , Sun Yat-sen University , Guangzhou , Guangdong Province , China
- Department of Oncology , The First Affiliated Hospital of Sun Yat-sen University , Guangzhou , Guangdong Province , China
| | - Alfred Sze-Lok Cheng
- School of Biomedical Sciences , The Chinese University of Hong Kong , Hong Kong , China
| | - Sui Peng
- Institute of Precision Medicine , the First Affiliated Hospital , Sun Yat-sen University , Guangzhou , Guangdong Province , China
- Department of Gastroenterology and Hepatology , The First Affiliated Hospital, Sun Yat-sen University , Guangzhou , Guangdong Province , China
- Clinical Trials Unit , The First Affiliated Hospital , Sun Yat-sen University , Guangzhou , Guangdong Province , China
| | - Shuibin Lin
- Institute of Precision Medicine , the First Affiliated Hospital , Sun Yat-sen University , Guangzhou , Guangdong Province , China
- Center for Translational Medicine , The First Affiliated Hospital , Sun Yat-sen University , Guangzhou , Guangdong Province , China
| | - Ji Wang
- Institute of Precision Medicine , the First Affiliated Hospital , Sun Yat-sen University , Guangzhou , Guangdong Province , China
| | - Shuling Chen
- Division of Interventional Ultrasound , The First Affiliated Hospital , Sun Yat-sen University , Guangzhou , Guangdong Province , China
| | - Ming Kuang
- Department of Liver Surgery , Center of Hepato-Pancreato-Biliary Surgery , The First Affiliated Hospital, Sun Yat-sen University , Guangzhou , Guangdong Province , China
- Institute of Precision Medicine , the First Affiliated Hospital , Sun Yat-sen University , Guangzhou , Guangdong Province , China
- Department of Oncology , The First Affiliated Hospital of Sun Yat-sen University , Guangzhou , Guangdong Province , China
- Division of Interventional Ultrasound , The First Affiliated Hospital , Sun Yat-sen University , Guangzhou , Guangdong Province , China
- Cancer Center , The First Affiliated Hospital , Sun Yat-sen University , Guangzhou , Guangdong Province , China
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24
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Chen C, Wang Z, Ding Y, Qin Y. Tumor microenvironment-mediated immune evasion in hepatocellular carcinoma. Front Immunol 2023; 14:1133308. [PMID: 36845131 PMCID: PMC9950271 DOI: 10.3389/fimmu.2023.1133308] [Citation(s) in RCA: 97] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 02/02/2023] [Indexed: 02/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the third leading cause of tumor-related mortality worldwide. In recent years, the emergency of immune checkpoint inhibitor (ICI) has revolutionized the management of HCC. Especially, the combination of atezolizumab (anti-PD1) and bevacizumab (anti-VEGF) has been approved by the FDA as the first-line treatment for advanced HCC. Despite great breakthrough in systemic therapy, HCC continues to portend a poor prognosis owing to drug resistance and frequent recurrence. The tumor microenvironment (TME) of HCC is a complex and structured mixture characterized by abnormal angiogenesis, chronic inflammation, and dysregulated extracellular matrix (ECM) remodeling, collectively contributing to the immunosuppressive milieu that in turn prompts HCC proliferation, invasion, and metastasis. The tumor microenvironment coexists and interacts with various immune cells to maintain the development of HCC. It is widely accepted that a dysfunctional tumor-immune ecosystem can lead to the failure of immune surveillance. The immunosuppressive TME is an external cause for immune evasion in HCC consisting of 1) immunosuppressive cells; 2) co-inhibitory signals; 3) soluble cytokines and signaling cascades; 4) metabolically hostile tumor microenvironment; 5) the gut microbiota that affects the immune microenvironment. Importantly, the effectiveness of immunotherapy largely depends on the tumor immune microenvironment (TIME). Also, the gut microbiota and metabolism profoundly affect the immune microenvironment. Understanding how TME affects HCC development and progression will contribute to better preventing HCC-specific immune evasion and overcoming resistance to already developed therapies. In this review, we mainly introduce immune evasion of HCC underlying the role of immune microenvironment, describe the dynamic interaction of immune microenvironment with dysfunctional metabolism and the gut microbiome, and propose therapeutic strategies to manipulate the TME in favor of more effective immunotherapy.
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Affiliation(s)
| | | | | | - Yanru Qin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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25
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Myeloid-derived suppressor cells: A new emerging player in endometriosis. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 375:191-220. [PMID: 36967153 DOI: 10.1016/bs.ircmb.2022.11.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Endometriosis is a common gynecological disorder defined by the presence of endometrial tissue outside the uterus. This is commonly associated with chronic pelvic pain, infertility, and dysmenorrhea, which occurs in approximately 10% of women of reproductive age. Although the exact mechanism remains uncertain, it has been widely accepted to be an estrogen-dependent and inflammatory disease. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immune cells with immunosuppressive capacity and non-immunological functions. They have been found to be aggressively involved in the pathologies of various disorders. In regards to tumors, the functions of MDSCs have been profoundly shown to inhibit tumor immune response and to promote angiogenesis, tumor metastasis, fibrosis, and epithelial-mesenchymal transition (EMT). In recent years, the elevation of MDSCs in endometriosis was reported by several studies that provoke the assumption that MDSCs might exert similar roles to promote the development of endometriosis. Such that, precision treatments targeting MDSCs might be a promising direction for future study. Herein, we will review the research progress of MDSCs in endometriosis and its potential relevance to the pathogenesis, progression, and therapeutics strategy of endometriosis.
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26
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Jianyi D, Haili G, Bo Y, Meiqin Y, Baoyou H, Haoran H, Fang L, Qingliang Z, Lingfei H. Myeloid-derived suppressor cells cross-talk with B10 cells by BAFF/BAFF-R pathway to promote immunosuppression in cervical cancer. Cancer Immunol Immunother 2023; 72:73-85. [PMID: 35725835 DOI: 10.1007/s00262-022-03226-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 05/17/2022] [Indexed: 01/07/2023]
Abstract
Immunosuppression induced by myeloid-derived suppressor cells (MDSCs) is one of the main obstacles to the efficacy of immunotherapy for cervical cancer. Recent studies on the immunosuppressive ability of MDSCs have primarily focused on T cells, but the effect of MDSCs on B cells function is still unclear. In a study of clinical specimens, we found that the accumulation of MDSCs in patients with cervical cancer was accompanied by high expression of B cell activating factor (BAFF) on the surface and high expression of interleukin (IL)-10-producing B cells (B10) in vivo. We found that the absence of BAFF could significantly inhibit tumor growth in a cervical cancer model using BAFF KO mice. Further studies showed that abundant MDSCs in cervical cancer induced B cells to differentiate into B10 cells by regulating BAFF which acted on the BAFF receptor (BAFF-R) of them. In this process, we found that a large amount of IL-10 secreted by B10 cells can activate STAT3 signaling pathway in MDSCs, and then form a positive feedback loop to promote the differentiation of B10 cells. Therefore, this study reveals a new mechanism of BAFF-mediated mutual immune regulation between MDSCs and B cells in the occurrence and development of cervical cancer.
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Affiliation(s)
- Ding Jianyi
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201240, China
| | - Gan Haili
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201240, China
| | - Yin Bo
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201240, China
| | - Yang Meiqin
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201240, China
| | - Huang Baoyou
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201240, China
| | - Hu Haoran
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201240, China
| | - Li Fang
- Department of Gynecology, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200120, China.
| | - Zheng Qingliang
- Sun Yat-sen University, Prenatal Diagnosis Center, The Eighth Affiliated Hospital, Shenzhen, 518000, People's Republic of China.
| | - Han Lingfei
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201240, China.
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27
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Glover A, Zhang Z, Shannon-Lowe C. Deciphering the roles of myeloid derived suppressor cells in viral oncogenesis. Front Immunol 2023; 14:1161848. [PMID: 37033972 PMCID: PMC10076641 DOI: 10.3389/fimmu.2023.1161848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 03/10/2023] [Indexed: 04/11/2023] Open
Abstract
Myeloid derived suppressor cells (MDSCs) are a heterogenous population of myeloid cells derived from monocyte and granulocyte precursors. They are pathologically expanded in conditions of ongoing inflammation where they function to suppress both innate and adaptive immunity. They are subdivided into three distinct subsets: monocytic (M-) MDSC, polymorphonuclear (or neutrophilic) (PMN-) MDSC and early-stage (e-) MDSC that may exhibit differential function in different pathological scenarios. However, in cancer they are associated with inhibition of the anti-tumour immune response and are universally associated with a poor prognosis. Seven human viruses classified as Group I carcinogenic agents are jointly responsible for nearly one fifth of all human cancers. These viruses represent a large diversity of species, including DNA, RNA and retroviridae. They include the human gammaherpesviruses (Epstein Barr virus (EBV) and Kaposi's Sarcoma-Associated Herpesvirus (KSHV), members of the high-risk human papillomaviruses (HPVs), hepatitis B and C (HBV, HCV), Human T cell leukaemia virus (HTLV-1) and Merkel cell polyomavirus (MCPyV). Each of these viruses encode an array of different oncogenes that perturb numerous cellular pathways that ultimately, over time, lead to cancer. A prerequisite for oncogenesis is therefore establishment of chronic infection whereby the virus persists in the host cells without being eradicated by the antiviral immune response. Although some of the viruses can directly modulate the immune response to enable persistence, a growing body of evidence suggests the immune microenvironment is modulated by expansions of MDSCs, driven by viral persistence and oncogenesis. It is likely these MDSCs play a role in loss of immune recognition and function and it is therefore essential to understand their phenotype and function, particularly given the increasing importance of immunotherapy in the modern arsenal of anti-cancer therapies. This review will discuss the role of MDSCs in viral oncogenesis. In particular we will focus upon the mechanisms thought to drive the MDSC expansions, the subsets expanded and their impact upon the immune microenvironment. Importantly we will explore how MDSCs may modulate current immunotherapies and their impact upon the success of future immune-based therapies.
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28
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Niu ZS, Wang WH, Niu XJ. Recent progress in molecular mechanisms of postoperative recurrence and metastasis of hepatocellular carcinoma. World J Gastroenterol 2022; 28:6433-6477. [PMID: 36569275 PMCID: PMC9782839 DOI: 10.3748/wjg.v28.i46.6433] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 10/31/2022] [Accepted: 11/21/2022] [Indexed: 12/08/2022] Open
Abstract
Hepatectomy is currently considered the most effective option for treating patients with early and intermediate hepatocellular carcinoma (HCC). Unfortunately, the postoperative prognosis of patients with HCC remains unsatisfactory, predominantly because of high postoperative metastasis and recurrence rates. Therefore, research on the molecular mechanisms of postoperative HCC metastasis and recurrence will help develop effective intervention measures to prevent or delay HCC metastasis and recurrence and to improve the long-term survival of HCC patients. Herein, we review the latest research progress on the molecular mechanisms underlying postoperative HCC metastasis and recurrence to lay a foundation for improving the understanding of HCC metastasis and recurrence and for developing more precise prevention and intervention strategies.
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Affiliation(s)
- Zhao-Shan Niu
- Laboratory of Micromorphology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Wen-Hong Wang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Xiao-Jun Niu
- Department of Internal Medicine, Qingdao Shibei District People's Hospital, Qingdao 266033, Shandong Province, China
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29
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Comparative analysis of the immune response to RFA and cryoablation in a colon cancer mouse model. Sci Rep 2022; 12:18229. [PMID: 36309550 PMCID: PMC9617942 DOI: 10.1038/s41598-022-22279-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 10/12/2022] [Indexed: 12/31/2022] Open
Abstract
The immune response to radiofrequency ablation (RFA) and cryoablation (CRA) was characterized and compared in a colon cancer mouse model. All studies were conducted under a research protocol approved by the National Institutes of Health, Clinical Center, Animal Care and Use Committee. BALB/cJ mice were inoculated with CT26 cells, and randomized to RFA, CRA, or sham treatment. Mice were sacrificed 3 days post-treatment, and tumor, spleen, and serum were harvested. Cell death was determined by Caspase-3 immunohistochemical and TUNEL stains. Immune response was analyzed using flow cytometry, serum cytokine assay and immunohistochemistry. Cell death, necrosis, and apoptosis induced by ablation were comparable in RFA and CRA. Decreased frequency of systemic T-regulatory cells was found in the CRA group. Both RFA and CRA reduced frequencies of several myeloid-derived suppressor cell (MDSC) subpopulations. RFA induced pro-inflammatory cytokine secretion including TNF-α and IL-12 as well as anti-inflammatory cytokines IL-5, and IL-10. CRA augmented secretion of a wider array of cytokines compared to RFA with both pro- and anti-inflammatory properties including IL-1β, IL-5, IL-6, IL-10, and KC GRO. In the tumor microenvironment, RFA reduced the number of T-regulatory cells, a finding not observed with CRA. Reduction of immune suppression via decreases in T-regulatory cells and MDSC was found to be induced by RFA or CRA. CRA augmented a wider range of cytokines than RFA, which were mainly pro-inflammatory, but also anti-inflammatory. In the tumor microenvironment, RFA demonstrated more pronounced anti-tumoral immunity. Further delineation of specific immunomodulation induced by ablation could inform drug-device development and may play a role in future hypothesis-driven immunomodulatory paradigms that combine immunotherapy drugs with tumor destruction for the treatment of metastatic colon cancer.
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30
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Cassese G, Han HS, Lee B, Lee HW, Cho JY, Panaro F, Troisi RI. Immunotherapy for hepatocellular carcinoma: A promising therapeutic option for advanced disease. World J Hepatol 2022; 14:1862-1874. [PMID: 36340753 PMCID: PMC9627435 DOI: 10.4254/wjh.v14.i10.1862] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/26/2022] [Accepted: 10/04/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, and its incidence continues to increase. Despite improvements in both medical and surgical therapies, HCC remains associated with poor outcomes due to its high rates of recurrence and mortality. Approximately 50% of patients require systemic therapies that traditionally consist of tyrosine kinase inhibitors. Recently, however, immune checkpoint inhibitors have revolutionized HCC management, providing new therapeutic options. Despite these major advances, the different factors involved in poor clinical responses and molecular pathways leading to resistance following use of these therapies remain unclear. Alternative strategies, such as adoptive T cell transfer, vaccination, and virotherapy, are currently under evaluation. Combinations of immunotherapies with other systemic or local treatments are also being investigated and may be the most promising opportunities for HCC treatment. The aim of this review is to provide updated information on currently available immunotherapies for HCC as well as future perspectives.
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Affiliation(s)
- Gianluca Cassese
- Department of Clinical Medicine and Surgery, Division of Minimally Invasive and Robotic HPB Surgery, Federico II University, Naples 80131, Italy
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
| | - Ho-Seong Han
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
| | - Boram Lee
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
| | - Hae Won Lee
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
| | - Jai Young Cho
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
| | - Fabrizio Panaro
- Department of Surgery, Division of HBP Surgery and Transplantation, Montpellier University Hospital - School of Medicine, Montpellier 34000, France
| | - Roberto Ivan Troisi
- Department of Clinical Medicine and Surgery, Division of Minimally Invasive and Robotic HPB Surgery, Federico II University, Naples 80131, Italy
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Feng H, Zhuo Y, Zhang X, Li Y, Li Y, Duan X, Shi J, Xu C, Gao Y, Yu Z. Tumor Microenvironment in Hepatocellular Carcinoma: Key Players for Immunotherapy. J Hepatocell Carcinoma 2022; 9:1109-1125. [PMID: 36320666 PMCID: PMC9618253 DOI: 10.2147/jhc.s381764] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 10/19/2022] [Indexed: 11/06/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains a serious medical therapeutic challenge as conventional curative avenues such as surgery and chemotherapy only benefit for few patients with limited tumor burden. Immunotherapy achieves clinical progress in the treatment of this prevalent malignant disease by virtue of the development of tumor immunology; however, most patients have experienced minimal or no clinical benefit in terms of overall survival. The complexity and diversity of tumor microenvironment (TME) built by immune and stromal cell subsets has been considered to be responsible for the insufficiency of immunotherapy. The advance of bioanalytical technology boosts the exploration of the composition and differentiation of these infiltrated cells, which reflect the immune state of the TME and impact the efficacy of the antitumor immune response. Targeting these cells to remodel the TME is one of the important immunotherapeutic approaches to improve HCC treatment. In this review, we focused on the role of these non-cancerous cells in the tumor progression, and elaborated their function on cancer immunotherapy when manipulating them as potential targets.
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Affiliation(s)
- Hai Feng
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Yunhui Zhuo
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Xuemei Zhang
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Yuyao Li
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Yue Li
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Xiangjuan Duan
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Jia Shi
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Chengbin Xu
- Department of Informatics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Yueqiu Gao
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China,Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China,Correspondence: Yueqiu Gao, Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China, Tel +86 21 20256507, Fax +86 21 20256699, Email
| | - Zhuo Yu
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China,Zhuo Yu, Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China, Tel +86 21 20256507, Fax +86 21 20256699, Email
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Wu Y, Yi M, Niu M, Mei Q, Wu K. Myeloid-derived suppressor cells: an emerging target for anticancer immunotherapy. Mol Cancer 2022; 21:184. [PMID: 36163047 PMCID: PMC9513992 DOI: 10.1186/s12943-022-01657-y] [Citation(s) in RCA: 198] [Impact Index Per Article: 66.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 09/19/2022] [Indexed: 02/07/2023] Open
Abstract
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.
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Affiliation(s)
- Yuze Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Ming Yi
- Department of Breast Surgery, Zhejiang University School of Medicine First Affiliated Hospital, Hangzhou, 310003, China
| | - Mengke Niu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Qi Mei
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China. .,Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China.
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China.
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Abstract
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.
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Affiliation(s)
- Yuze Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Ming Yi
- Department of Breast Surgery, Zhejiang University School of Medicine First Affiliated Hospital, Hangzhou, 310003, China
| | - Mengke Niu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Qi Mei
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China.
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China.
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China.
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Foerster F, Gairing SJ, Ilyas SI, Galle PR. Emerging immunotherapy for HCC: A guide for hepatologists. Hepatology 2022; 75:1604-1626. [PMID: 35253934 PMCID: PMC9117522 DOI: 10.1002/hep.32447] [Citation(s) in RCA: 146] [Impact Index Per Article: 48.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 01/31/2022] [Accepted: 01/31/2022] [Indexed: 12/12/2022]
Abstract
HCC is one of the most common cancers worldwide, and the third leading cause of cancer-related death globally. HCC comprises nearly 90% of all cases of primary liver cancer. Approximately half of all patients with HCC receive systemic therapy during their disease course, particularly in the advanced stages of disease. Immuno-oncology has been paradigm shifting for the treatment of human cancers, with strong and durable antitumor activity in a subset of patients across a variety of malignancies including HCC. Immune checkpoint inhibition with atezolizumab and bevacizumab, an antivascular endothelial growth factor neutralizing antibody, has become first-line therapy for patients with advanced HCC. Beyond immune checkpoint inhibition, immunotherapeutic strategies such as oncolytic viroimmunotherapy and adoptive T-cell transfer are currently under investigation. The tumor immune microenvironment of HCC has significant immunosuppressive elements that may affect response to immunotherapy. Major unmet challenges include defining the role of immunotherapy in earlier stages of HCC, evaluating combinatorial strategies that use targeting of the immune microenvironment plus immune checkpoint inhibition, and identifying treatment strategies for patients who do not respond to the currently available immunotherapies. Herein, we review the rationale, mechanistic basis and supporting preclinical evidence, and available clinical evidence for immunotherapies in HCC as well as ongoing clinical trials of immunotherapy.
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Affiliation(s)
- Friedrich Foerster
- Department of Medicine I, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany
| | - Simon Johannes Gairing
- Department of Medicine I, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany
| | - Sumera Irie Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Peter Robert Galle
- Department of Medicine I, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany
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Zhang Y, Brekken RA. Direct and indirect regulation of the tumor immune microenvironment by VEGF. J Leukoc Biol 2022; 111:1269-1286. [DOI: 10.1002/jlb.5ru0222-082r] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/06/2022] [Accepted: 04/07/2022] [Indexed: 12/19/2022] Open
Affiliation(s)
- Yuqing Zhang
- Hamon Center for Therapeutic Oncology Research UT Southwestern Medical Center Dallas Texas USA
- Department of Surgery UT Southwestern Medical Center Dallas Texas USA
- Cancer Biology Graduate Program UT Southwestern Medical Center Dallas Texas USA
- Current affiliation: Department of Medical Oncology Dana‐Farber Cancer Institute Boston Massachusetts USA
| | - Rolf A. Brekken
- Hamon Center for Therapeutic Oncology Research UT Southwestern Medical Center Dallas Texas USA
- Department of Surgery UT Southwestern Medical Center Dallas Texas USA
- Cancer Biology Graduate Program UT Southwestern Medical Center Dallas Texas USA
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Liver-specific overexpression of Gab2 accelerates hepatocellular carcinoma progression by activating immunosuppression of myeloid-derived suppressor cells. Oncogene 2022; 41:3316-3327. [DOI: 10.1038/s41388-022-02298-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 03/20/2022] [Accepted: 03/24/2022] [Indexed: 12/09/2022]
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Tamadaho RSE, Ritter M, Wiszniewsky A, Arndts K, Mack M, Hoerauf A, Layland LE. Infection-Derived Monocytic MDSCs Require TGF-β to Suppress Filarial-Specific IFN-γ But Not IL-13 Release by Filarial-Specific CD4+ T Cells In Vitro. FRONTIERS IN TROPICAL DISEASES 2022. [DOI: 10.3389/fitd.2021.707100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Lymphatic filariasis (LF) remains a major health problem with severe economic repercussions in endemic communities of Sub-saharan Africa, South-East Asia and South America. The rodent-specific nematode Litomosoides sigmodontis (Ls) is used to study the immunomodulatory potential of filariae and research has elucidated pathways involving regulatory T cells (Tregs), IL-10 producing cells and alternatively activated macrophages (AAMs) and that CD4+ T cells play a paramount role during infection. Myeloid-derived suppressor cells (MDSCs) have been identified and characterised in man in cancer and other pathologies. The hallmark of MDSC populations is the suppression of T and B cell responses using various mechanisms, which are mostly specific to the pathology or setting. However, until now, it remains unclear whether they play a role in filarial-specific responses. We report here that monocytic MDSCs (Mo-MDSCs, CD11b+Ly6C+Ly6G-) and polymorphonuclear MDSCs (PMN-MDSCs, CD11b+Ly6Cint/loLy6G+) expanded in the thoracic cavity (TC, the site of infection) and correlated positively with filarial life-stages in Ls-infected BALB/c mice. In vitro, only infection-derived Mo-MDSCs showed a suppressive nature by preventing IL-13 and IFN-γ secretion from filarial-specific CD4+ T cells upon co-culture with soluble worm extract. This suppression was not mediated by IL-10, IL-6 or TNF-α, and did not require cell-contact, nitric oxide (NO), IL-4/IL-5 signalling pathways or CCR2. Interestingly, neutralizing TGF-β significantly rescued IFN-γ but not IL-13 production by filarial-specific CD4+ T cells. In comparison to naive cells, PCR array data showed an overall down-regulation of inflammatory pathways in both infection-derived Mo-MDSCs and PMN-MDSCs. In conclusion, these primary data sets show activity and expansion of MDSCs during Ls infection adding this regulatory cell type to the complex milieu of host responses during chronic helminth infections.
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Bayik D, Lee J, Lathia JD. The Role of Myeloid-Derived Suppressor Cells in Tumor Growth and Metastasis. EXPERIENTIA SUPPLEMENTUM (2012) 2022; 113:189-217. [PMID: 35165865 DOI: 10.1007/978-3-030-91311-3_7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Myeloid-derived suppressor cells (MDSCs) are immature bone marrow-derived suppressive cells that are an important component of the pathological immune response associated with cancer. Expansion of MDSCs has been linked to poor disease outcome and therapeutic resistance in patients with various malignancies, making these cells potential targets for next-generation treatment strategies. MDSCs are classified into monocytic (M-MDSC) and polymorphonuclear/granulocytic (PMN-MDSC) subtypes that undertake distinct and numerous roles in the tumor microenvironment or systemically to drive disease progression. In this chapter, we will discuss how MDSC subsets contribute to the growth of primary tumors and induce metastatic spread by suppressing the antitumor immune response, supporting cancer stem cell (CSC)/epithelial-to-mesenchymal transition (EMT) phenotypes and promoting angiogenesis. We will also summarize the signaling networks involved in the crosstalk between cancer cells and MDSCs that could represent putative immunotherapy targets.
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Affiliation(s)
- Defne Bayik
- Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.,Case Comprehensive Cancer Center, Euclid, OH, USA
| | - Juyeun Lee
- Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Justin D Lathia
- Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. .,Case Comprehensive Cancer Center, Euclid, OH, USA.
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Therapeutic Vaccines against Hepatocellular Carcinoma in the Immune Checkpoint Inhibitor Era: Time for Neoantigens? Int J Mol Sci 2022; 23:ijms23042022. [PMID: 35216137 PMCID: PMC8875127 DOI: 10.3390/ijms23042022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/07/2022] [Accepted: 02/10/2022] [Indexed: 02/01/2023] Open
Abstract
Immune checkpoint inhibitors (ICI) have been used as immunotherapy for hepatocellular carcinoma (HCC) with promising but still limited results. Identification of immune elements in the tumor microenvironment of individual HCC patients may help to understand the correlations of responses, as well as to design personalized therapies for non-responder patients. Immune-enhancing strategies, such as vaccination, would complement ICI in those individuals with poorly infiltrated tumors. The prominent role of responses against mutated tumor antigens (neoAgs) in ICI-based therapies suggests that boosting responses against these epitopes may specifically target tumor cells. In this review we summarize clinical vaccination trials carried out in HCC, the available information on potentially immunogenic neoAgs in HCC patients, and the most recent results of neoAg-based vaccines in other tumors. Despite the low/intermediate mutational burden observed in HCC, data obtained from neoAg-based vaccines in other tumors indicate that vaccines directed against these tumor-specific antigens would complement ICI in a subset of HCC patients.
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40
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Gorzo A, Galos D, Volovat SR, Lungulescu CV, Burz C, Sur D. Landscape of Immunotherapy Options for Colorectal Cancer: Current Knowledge and Future Perspectives beyond Immune Checkpoint Blockade. Life (Basel) 2022; 12:229. [PMID: 35207516 PMCID: PMC8878674 DOI: 10.3390/life12020229] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/21/2022] [Accepted: 01/31/2022] [Indexed: 11/24/2022] Open
Abstract
Colorectal cancer is the third most prevalent malignancy in Western countries and a major cause of death despite recent improvements in screening programs and early detection methods. In the last decade, a growing effort has been put into better understanding how the immune system interacts with cancer cells. Even if treatments with immune checkpoint inhibitors (anti-PD1, anti-PD-L1, anti-CTLA4) were proven effective for several cancer types, the benefit for colorectal cancer patients is still limited. However, a subset of patients with deficient mismatch repair (dMMR)/microsatellite-instability-high (MSI-H) metastatic colorectal cancer has been observed to have a prolonged benefit to immune checkpoint inhibitors. As a result, pembrolizumab and nivolumab +/- ipilimumab recently obtained the Food and Drug Administration approval. This review aims to highlight the body of knowledge on immunotherapy in the colorectal cancer setting, discussing the potential mechanisms of resistance and future strategies to extend its use.
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Affiliation(s)
- Alecsandra Gorzo
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuţă”, 400015 Cluj-Napoca, Romania; (A.G.); (D.G.); (C.B.)
- Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400000 Cluj-Napoca, Romania
| | - Diana Galos
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuţă”, 400015 Cluj-Napoca, Romania; (A.G.); (D.G.); (C.B.)
- Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400000 Cluj-Napoca, Romania
| | - Simona Ruxandra Volovat
- Department of Medical Oncology, University of Medicine and Pharmacy “Grigore T. Popa” Iasi, 700115 Iasi, Romania;
| | | | - Claudia Burz
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuţă”, 400015 Cluj-Napoca, Romania; (A.G.); (D.G.); (C.B.)
- Department of Allergology and Immunology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400000 Cluj-Napoca, Romania
| | - Daniel Sur
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuţă”, 400015 Cluj-Napoca, Romania; (A.G.); (D.G.); (C.B.)
- Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400000 Cluj-Napoca, Romania
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Ma T, Renz BW, Ilmer M, Koch D, Yang Y, Werner J, Bazhin AV. Myeloid-Derived Suppressor Cells in Solid Tumors. Cells 2022; 11:cells11020310. [PMID: 35053426 PMCID: PMC8774531 DOI: 10.3390/cells11020310] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/03/2022] [Accepted: 01/11/2022] [Indexed: 12/12/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are one of the main suppressive cell population of the immune system. They play a pivotal role in the establishment of the tumor microenvironment (TME). In the context of cancers or other pathological conditions, MDSCs can differentiate, expand, and migrate in large quantities during circulation, inhibiting the cytotoxic functions of T cells and NK cells. This process is regulated by ROS, iNOS/NO, arginase-1, and multiple soluble cytokines. The definition of MDSCs and their phenotypes in humans are not as well represented as in other organisms such as mice, owing to the absence of the cognate molecule. However, a comprehensive understanding of the differences between different species and subsets will be beneficial for clarifying the immunosuppressive properties and potential clinical values of these cells during tumor progression. Recently, experimental evidence and clinical investigations have demonstrated that MDSCs have a close relationship with poor prognosis and drug resistance, which is considered to be a leading marker for practical applications and therapeutic methods. In this review, we summarize the remarkable position of MDSCs in solid tumors, explain their classifications in different models, and introduce new treatment approaches to target MDSCs to better understand the advancement of new approaches to cancer treatment.
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Affiliation(s)
- Tianmiao Ma
- Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany; (T.M.); (B.W.R.); (M.I.); (D.K.); (J.W.)
| | - Bernhard W. Renz
- Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany; (T.M.); (B.W.R.); (M.I.); (D.K.); (J.W.)
- German Cancer Consortium (DKTK), Partner Site Munich, 81377 Munich, Germany
| | - Matthias Ilmer
- Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany; (T.M.); (B.W.R.); (M.I.); (D.K.); (J.W.)
- German Cancer Consortium (DKTK), Partner Site Munich, 81377 Munich, Germany
| | - Dominik Koch
- Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany; (T.M.); (B.W.R.); (M.I.); (D.K.); (J.W.)
| | - Yuhui Yang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China;
| | - Jens Werner
- Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany; (T.M.); (B.W.R.); (M.I.); (D.K.); (J.W.)
- German Cancer Consortium (DKTK), Partner Site Munich, 81377 Munich, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Alexandr V. Bazhin
- Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany; (T.M.); (B.W.R.); (M.I.); (D.K.); (J.W.)
- German Cancer Consortium (DKTK), Partner Site Munich, 81377 Munich, Germany
- Correspondence:
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Aoki T, Nishida N, Kudo M. Current Perspectives on the Immunosuppressive Niche and Role of Fibrosis in Hepatocellular Carcinoma and the Development of Antitumor Immunity. J Histochem Cytochem 2022; 70:53-81. [PMID: 34751050 PMCID: PMC8721576 DOI: 10.1369/00221554211056853] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Immune checkpoint inhibitors have become the mainstay of treatment for hepatocellular carcinoma (HCC). However, they are ineffective in some cases. Previous studies have reported that genetic alterations in oncogenic pathways such as Wnt/β-catenin are the important triggers in HCC for primary refractoriness. T-cell exhaustion has been reported in various tumors and is likely to play a prominent role in the emergence of HCC due to chronic inflammation and cirrhosis-associated immune dysfunction. Immunosuppressive cells including regulatory T-cells and tumor-associated macrophages infiltrating the tumor are associated with hyperprogressive disease in the early stages of immune checkpoint inhibitor treatment. In addition, stellate cells and tumor-associated fibroblasts create an abundant desmoplastic environment by producing extracellular matrix. This strongly contributes to epithelial to mesenchymal transition via signaling activities including transforming growth factor beta, Wnt/β-catenin, and Hippo pathway. The abundant desmoplastic environment has been demonstrated in pancreatic ductal adenocarcinoma and cholangiocarcinoma to suppress cytotoxic T-cell infiltration, PD-L1 expression, and neoantigen expression, resulting in a highly immunosuppressive niche. It is possible that a similar immunosuppressive environment is created in HCC with advanced fibrosis in the background liver. Although sufficient understanding is required for the establishment of immune therapies of HCC, further investigations are still required in this field.
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Affiliation(s)
- Tomoko Aoki
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan
| | - Naoshi Nishida
- Naoshi Nishida, Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-Sayama 589-8511, Japan. E-mail:
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan
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Ozer M, George A, Goksu SY, George T, Sahin I. The Role of Immune Checkpoint Blockade in the Hepatocellular Carcinoma: A Review of Clinical Trials. Front Oncol 2021; 11:801379. [PMID: 34956912 PMCID: PMC8692256 DOI: 10.3389/fonc.2021.801379] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 11/22/2021] [Indexed: 12/12/2022] Open
Abstract
The prevalence of primary liver cancer is rapidly rising all around the world. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Unfortunately, the traditional treatment methods to cure HCC showed poor efficacy in patients who are not candidates for liver transplantation. Until recently, tyrosine kinase inhibitors (TKIs) were the front-line treatment for unresectable liver cancer. However, rapidly emerging new data has drastically changed the landscape of HCC treatment. The combination treatment of atezolizumab plus bevacizumab (immunotherapy plus anti-VEGF) was shown to provide superior outcomes and has become the new standard first-line treatment for unresectable or metastatic HCC. Currently, ongoing clinical trials with immune checkpoint blockade (ICB) have focused on assessing the benefit of antibodies against programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4) as monotherapies or combination therapies in patients with HCC. In this review, we briefly discuss the mechanisms underlying various novel immune checkpoint blockade therapies and combination modalities along with recent/ongoing clinical trials which may generate innovative new treatment approaches with potential new FDA approvals for HCC treatment in the near future.
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Affiliation(s)
- Muhammet Ozer
- Department of Internal Medicine, Capital Health Medical Center, Trenton, NJ, United States
| | - Andrew George
- Department of Chemistry, Brown University, Providence, RI, United States
- Department of Molecular Biology, Cell Biology & Biochemistry, Division of Biology and Medicine, Brown University, Providence, RI, United States
| | - Suleyman Yasin Goksu
- Division of Hematology/Oncology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Thomas J. George
- Division of Hematology/Oncology, Department of Medicine, University of Florida, Gainesville, FL, United States
- Division of Hematology/Oncology, Department of Medicine, University of Florida Health Cancer Center, Gainesville, FL, United States
| | - Ilyas Sahin
- Division of Hematology/Oncology, Department of Medicine, University of Florida, Gainesville, FL, United States
- Division of Hematology/Oncology, Department of Medicine, University of Florida Health Cancer Center, Gainesville, FL, United States
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Hao X, Sun G, Zhang Y, Kong X, Rong D, Song J, Tang W, Wang X. Targeting Immune Cells in the Tumor Microenvironment of HCC: New Opportunities and Challenges. Front Cell Dev Biol 2021; 9:775462. [PMID: 34869376 PMCID: PMC8633569 DOI: 10.3389/fcell.2021.775462] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 10/19/2021] [Indexed: 12/17/2022] Open
Abstract
Immune associated cells in the microenvironment have a significant impact on the development and progression of hepatocellular carcinoma (HCC) and have received more and more attention. Different types of immune-associated cells play different roles, including promoting/inhibiting HCC and several different types that are controversial. It is well known that immune escape of HCC has become a difficult problem in tumor therapy. Therefore, in recent years, a large number of studies have focused on the immune microenvironment of HCC, explored many mechanisms worth identifying tumor immunosuppression, and developed a variety of immunotherapy methods as targets, laying the foundation for the final victory in the fight against HCC. This paper reviews recent studies on the immune microenvironment of HCC that are more reliable and important, and provides a more comprehensive view of the investigation of the immune microenvironment of HCC and the development of more immunotherapeutic approaches based on the relevant summaries of different immune cells.
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Affiliation(s)
- Xiaopei Hao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
| | - Guangshun Sun
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yao Zhang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
| | - Xiangyi Kong
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
| | - Dawei Rong
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
| | - Jinhua Song
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
| | - Weiwei Tang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
| | - Xuehao Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
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Neutrophils: Driving inflammation during the development of hepatocellular carcinoma. Cancer Lett 2021; 522:22-31. [PMID: 34517084 DOI: 10.1016/j.canlet.2021.09.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 09/05/2021] [Accepted: 09/07/2021] [Indexed: 12/13/2022]
Abstract
The relationship between immune and inflammatory responses in hepatocellular carcinoma (HCC) has garnered significant interest. In the peripheral blood and tumour microenvironment (TME), neutrophils, which are innate immune cells, crucially respond to various inflammatory factors, leading to tumour progression. To some extent, they affect the clinical treatment strategy and survival among HCC patients. A high circulating neutrophil-to-lymphocyte ratio is a reliable factor that can be used to predict poor outcomes in HCC patients. However, the mechanisms underlying the protumoural effects of circulating neutrophils remain poorly understood. Besides, the distinct role and function of neutrophils at the site of HCC remain relatively unclear, which is partially attributed to their substantial heterogeneity compared with other immune cells. In this review, we firstly discuss the current information available, detailing distinct subsets, functional phenotypes, and the impact of circulating and tumour-infiltrating neutrophils on tumourigenesis in HCC. Furthermore, we describe recent pre-clinical and clinical studies concerning neutrophils for evaluating the feasibility of targeting diverse protumoural aspects to improve therapeutic efficacy, thus paving the way for neutrophil-based treatment, especially in combination with immunotherapy.
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Feng XY, Chen BC, Li JC, Li JM, Li HM, Chen XQ, Liu D, Li RT. Gansui-Banxia Decoction extraction inhibits MDSCs accumulation via AKT /STAT3/ERK signaling pathways to regulate antitumor immunity in C57bl/6 mice. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 93:153779. [PMID: 34638030 DOI: 10.1016/j.phymed.2021.153779] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 09/16/2021] [Accepted: 09/25/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Gansui-Banxia Decoction (GSBXD) is a classic formula of traditional Chinese medical (TCM) sage Zhang Zhongjing to treat stagnation of evil heat and obstruction of qi. At present GSBXD is wildly used to treat cancerous ascites, pleural effusion, peritoneal effusion, pericardial effusion, cranial cavity effusion and several types of cancers, such as hepatocellular carcinoma (HCC) and esophageal cancer. Myeloid-derived suppressor cells (MDSCs) are a kind of immature and heterogeneous cells which can suppress lymphocytes activation by forming a suppressive environment. MDSCs accumulation in peripheral blood and tumors are closely related to the cancer stage and low survival rate of clinical patients. The antitumor immune effect of GSBXD has not received widespread attention. PURPOSE To investigate the effects of GSBXD on MDSCs accumulation and the mediators including AKT/STAT3/ERK signaling pathways. METHODS The chemical components of GSBXD were analyzed by UHPLC-MS, and the putative pathways of GSBXD based on Network pharmacology were predicted. Mice were vaccinated with Hepatoma 22 (H22) to establish tumor growth model, which were then administrated with GSBXD ethanol extraction (0.49 mg/kg/day, 1.75 mg/kg/day), sorafenib (60 mg/kg) or saline for 14 days. The cell morphology was evaluated by hematoxylin and eosin (H&E) staining, and immunity cells were determined through flowcytometry analysis. The levels of cytokines production in blood were evaluated by using ELISA kits. STAT3, ERK and AKT/mTOR signaling transduction associated proteins were determined by Western blot. RESULTS GSBXD could inhibit tumor growth and splenomegaly in H22 tumor model mice. Importantly, GSBXD reduced MDSCs accumulation and differentiation, and inhibited proliferation of F4/80+ CD11b+ macrophages and apoptosis of T cells and B cells, and increased the percentage of CD 3- NK1.1+ NK cells. To better understand the active component of GSBXD, the ethanol-extraction powdered GSBXD was prepared and analyzed by UHPLC-MS. Combined with these main chemical compounds, we predicted that the anti-tumor effect of GSBXD mainly mediated PI3K-AKT and RAS-MAPK signal pathways based on Network Pharmacology. Western blot analysis of tumor tissues and MDSCs cells demonstrated that phosphorylation of AKT, ERK and STAT3 were significantly reduced, specially the activation of ERK. The levels of IL-1β and IFN-γ were significantly decreased by ELISA analysis. CONCLUSION GSBXD exhibited antitumor immune activity by reducing the accumulation of MDSCs in vivo, which is possible via down-regulation of AKT/STAT3/ERK signaling pathway and suppression of IL-1β and IFN-γ.
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Affiliation(s)
- Xiao-Yi Feng
- Center for Pharmaceutical Sciences and Engineering, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, Yunnan, PR China; Faculty of basic Medicine, Yunnan University of Chinese Medicine, Kunming, 650500 Yunnan, PR China
| | - Bi-Chun Chen
- Center for Pharmaceutical Sciences and Engineering, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, Yunnan, PR China
| | - Jian-Chun Li
- Center for Pharmaceutical Sciences and Engineering, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, Yunnan, PR China
| | - Jin-Mei Li
- Center for Pharmaceutical Sciences and Engineering, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, Yunnan, PR China
| | - Hong-Mei Li
- Center for Pharmaceutical Sciences and Engineering, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, Yunnan, PR China
| | - Xuan-Qin Chen
- Center for Pharmaceutical Sciences and Engineering, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, Yunnan, PR China
| | - Dan Liu
- Center for Pharmaceutical Sciences and Engineering, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, Yunnan, PR China.
| | - Rong-Tao Li
- Center for Pharmaceutical Sciences and Engineering, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, Yunnan, PR China.
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Sharma V, Sachdeva N, Gupta V, Nada R, Jacob J, Sahni D, Aggarwal A. IL-6 is associated with expansion of myeloid-derived suppressor cells and enhanced immunosuppression in pancreatic adenocarcinoma patients. Scand J Immunol 2021; 94:e13107. [PMID: 38192074 DOI: 10.1111/sji.13107] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 09/30/2021] [Accepted: 10/05/2021] [Indexed: 01/05/2023]
Abstract
Chronic inflammation favours the expansion of myeloid-derived suppressor cells (MDSCs) by secreting pro-inflammatory mediators. The role of MDSCs in mediating immunosuppression in pancreatic adenocarcinoma and in defining a premalignant route from chronic pancreatitis remains unclear. We aimed to study the immunosuppressive potential of all subsets of MDSCs and their correlation with inflammatory cytokines in pancreatic adenocarcinoma and chronic pancreatitis. Relative frequencies of MDSCs, immunosuppressive markers arginase-1 (ARG-1), programmed death-ligand 1 (PD-L1), reactive oxygen species (ROS) and cytokines in circulation and surgically resected local pancreatic tissue of chronic pancreatitis and pancreatic adenocarcinoma patients were analysed by multicolour flow cytometry and cytokine bead array, respectively. Levels of cytokines involved in MDSCs activation were analysed by ELISA, and the immunosuppressive nature of MDSCs was confirmed by T-cell suppression assay. Frequencies of circulating MDSCs and ARG-1, PD-L1, and ROS were significantly higher in pancreatic adenocarcinoma than healthy controls and showed a significant positive correlation with MDSCs burden in cancer tissue. Serum levels of cytokines IL-6, IL-8 and IL-10 were significantly elevated in pancreatic adenocarcinoma. IL-6 serum levels showed a significant positive correlation with frequencies of circulating MDSCs in pancreatic adenocarcinoma patients, and MDSCs mediated suppression of T-cell proliferation in vitro was associated with elevated IL-6 levels in the cell culture medium. Collectively, our results suggest that IL-6 plays a crucial role in the expansion of MDSCs and activating their immunosuppressive nature in pancreatic adenocarcinoma. The relative frequency of MDSCs in circulation can be used as a potential diagnostic biomarker for pancreatic cancer.
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Affiliation(s)
- Vinit Sharma
- Department of Anatomy, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Naresh Sachdeva
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Vikas Gupta
- Department of Surgical Gastroenterology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Ritambhra Nada
- Department of Histopathology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Justin Jacob
- Department of Anatomy, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Daisy Sahni
- Department of Anatomy, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Anjali Aggarwal
- Department of Anatomy, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
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Bioinformatic Evidence Reveals that Cell Cycle Correlated Genes Drive the Communication between Tumor Cells and the Tumor Microenvironment and Impact the Outcomes of Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2021; 2021:4092635. [PMID: 34746301 PMCID: PMC8564189 DOI: 10.1155/2021/4092635] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Accepted: 09/04/2021] [Indexed: 12/27/2022]
Abstract
Hepatocellular carcinoma (HCC) is an aggressive cancer type with poor prognosis; thus, there is especially necessary and urgent to screen potential prognostic biomarkers for early diagnosis and novel therapeutic targets. In this study, we downloaded target data sets from the GEO database, and obtained codifferentially expressed genes using the limma R package and identified key genes through the protein–protein interaction network and molecular modules, and performed GO and KEGG pathway analyses for key genes via the clusterProfiler package and further determined their correlations with clinicopathological features using the Oncomine database. Survival analysis was completed in the GEPIA and the Kaplan–Meier plotter database. Finally, correlations between key genes, cell types infiltrated in the tumor microenvironment (TME), and hypoxic signatures were explored based on the TIMER database. From the results, 11 key genes related to the cell cycle were determined, and high levels of these key genes' expression were focused on advanced and higher grade status HCC patients, as well as in samples of TP53 mutation and vascular invasion. Besides, the 11 key genes were significantly associated with poor prognosis of HCC and also were positively related to the infiltration level of MDSCs in the TME and the HIF1A and VEGFA of hypoxic signatures, but a negative correlation was found with endothelial cells (ECs) and hematopoietic stem cells. The result determined that 11 key genes (RRM2, NDC80, ECT2, CCNB1, ASPM, CDK1, PRC1, KIF20A, DTL, TOP2A, and PBK) could play a vital role in the pathogenesis of HCC, drive the communication between tumor cells and the TME, and act as probably promising diagnostic, therapeutic, and prognostic biomarkers in HCC patients.
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Market M, Tennakoon G, Auer RC. Postoperative Natural Killer Cell Dysfunction: The Prime Suspect in the Case of Metastasis Following Curative Cancer Surgery. Int J Mol Sci 2021; 22:ijms222111378. [PMID: 34768810 PMCID: PMC8583911 DOI: 10.3390/ijms222111378] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 10/02/2021] [Accepted: 10/06/2021] [Indexed: 12/12/2022] Open
Abstract
Surgical resection is the foundation for the curative treatment of solid tumors. However, metastatic recurrence due to the difficulty in eradicating micrometastases remain a feared outcome. Paradoxically, despite the beneficial effects of surgical removal of the primary tumor, the physiological stress resulting from surgical trauma serves to promote cancer recurrence and metastasis. The postoperative environment suppresses critical anti-tumor immune effector cells, including Natural Killer (NK) cells. The literature suggests that NK cells are critical mediators in the formation of metastases immediately following surgery. The following review will highlight the mechanisms that promote the formation of micrometastases by directly or indirectly inducing NK cell suppression following surgery. These include tissue hypoxia, neuroendocrine activation, hypercoagulation, the pro-inflammatory phase, and the anti-inflammatory phase. Perioperative therapeutic strategies designed to prevent or reverse NK cell dysfunction will also be examined for their potential to improve cancer outcomes by preventing surgery-induced metastases.
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Affiliation(s)
- Marisa Market
- Faculty of Medicine, University of Ottawa, Ottawa, ON K1G 8M5, Canada; (M.M.); (G.T.)
- The Ottawa Hospital Research Institute, Ottawa, ON K1G 4E3, Canada
| | - Gayashan Tennakoon
- Faculty of Medicine, University of Ottawa, Ottawa, ON K1G 8M5, Canada; (M.M.); (G.T.)
| | - Rebecca C. Auer
- The Ottawa Hospital Research Institute, Ottawa, ON K1G 4E3, Canada
- Department of General Surgery, The Ottawa Hospital, Ottawa, ON K1Y 4E9, Canada
- Correspondence: ; Tel.: +1-613-722-7000
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Therapeutic Values of Myeloid-Derived Suppressor Cells in Hepatocellular Carcinoma: Facts and Hopes. Cancers (Basel) 2021; 13:cancers13205127. [PMID: 34680276 PMCID: PMC8534227 DOI: 10.3390/cancers13205127] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 10/05/2021] [Accepted: 10/06/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Myeloid-derived suppressor cells restrict the effectiveness of immune-checkpoint inhibitors for a subset of patients mainly through thwarting T cell infiltration into tumor sites. Treatments targeting MDSCs have shown potent inhibitory effects on multiple tumors, including hepatocellular carcinoma. In this review, we summarize the pathological mechanisms of MDSCs and their clinical significance as prognostic and predictive biomarkers for HCC patients, and we provide the latest progress of MDSCs-targeting treatment in HCC. Abstract One of the major challenges in hepatocellular carcinoma (HCC) treatment is drug resistance and low responsiveness to systemic therapies, partly due to insufficient T cell infiltration. Myeloid-derived suppressor cells (MDSCs) are immature marrow-derived cell populations with heterogeneity and immunosuppression characteristics and are essential components of the suppressive tumor immune microenvironment (TIME). Increasing evidence has demonstrated that MDSCs are indispensable contributing factors to HCC development in a T cell-dependent or non-dependent manner. Clinically, the frequency of MDSCs is firmly linked to HCC clinical outcomes and the effectiveness of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs). Furthermore, MDSCs can also be used as prognostic and predictive biomarkers for patients with HCC. Therefore, treatments reprograming MDSCs may offer potential therapeutic opportunities in HCC. Here, we recapitulated the dynamic relevance of MDSCs in the initiation and development of HCC and paid special attention to the effect of MDSCs on T cells infiltration in HCC. Finally, we pointed out the potential therapeutic effect of targeting MDSCs alone or in combination, hoping to provide new insights into HCC treatment.
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