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Ryba-Stanisławowska M. Unraveling Th subsets: insights into their role in immune checkpoint inhibitor therapy. Cell Oncol (Dordr) 2025; 48:295-312. [PMID: 39325360 PMCID: PMC11996958 DOI: 10.1007/s13402-024-00992-0] [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] [Accepted: 09/13/2024] [Indexed: 09/27/2024] Open
Abstract
T helper (Th) cell subsets play pivotal roles in regulating immune responses within the tumor microenvironment, influencing both tumor progression and anti-tumor immunity. Among these subsets, Th1 cells promote cytotoxic responses through the production of IFN-γ, while Th2 cells and regulatory T cells (Tregs) exert immunosuppressive effects that support tumor growth. Th9 and Th17 cells have context-dependent roles, contributing to both pro-inflammatory and regulatory processes in tumor immunity. Tumor antigen-specific T cells within the tumor microenvironment often exhibit a dysfunctional phenotype due to increased expression of inhibitory receptors such as CTLA-4 and PD-1, leading to reduced antitumor activity. Monoclonal antibodies that block these inhibitory signals-collectively known as immune checkpoint inhibitors (ICIs)-can reactivate these T cells, enhancing their ability to target and destroy cancer cells. Recent advancements have highlighted the critical role of T helper subsets in modulating responses to ICIs, with their interactions remaining a focus of ongoing research. Both positive and negative effects of ICIs have been reported in relation to Th cell subsets, with some effects depending on the type of tumor microenvironment. This review summarizes the crucial roles of different T helper cell subsets in tumor immunity and their complex relationship with immune checkpoint inhibitor therapy.
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Affiliation(s)
- Monika Ryba-Stanisławowska
- Department of Medical Immunology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 1, Gdańsk, 80-211, Poland.
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Liu P, Sun Z. Chemokines and their receptors in the esophageal carcinoma tumor microenvironment: key factors for metastasis and progression. Front Oncol 2025; 15:1523751. [PMID: 40134607 PMCID: PMC11933060 DOI: 10.3389/fonc.2025.1523751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 02/21/2025] [Indexed: 03/27/2025] Open
Abstract
Esophageal carcinoma (ESCA) is a highly malignant tumor with the highest incidence in Eastern Asia. Although treatment modalities for ESCA have advanced in recent years, the overall prognosis remains poor, as most patients are diagnosed at an advanced stage of the disease. There is an urgent need to promote early screening for ESCA to increase survival rates and improve patient outcomes. The development of ESCA is closely linked to the complex tumor microenvironment (TME), where chemokines and their receptors play pivotal roles. Chemokines are a class of small-molecule, secreted proteins and constitute the largest family of cytokines. They not only directly regulate tumor growth and proliferation but also influence cell migration and localization through specific receptor interactions. Consequently, chemokines and their receptors affect tumor invasion and metastatic spread. Furthermore, chemokines regulate immune cells, including macrophages and regulatory T cells, within the TME. The recruitment of these immune cells further leads to immunosuppression, creating favorable conditions for tumor growth and metastasis. This review examines the impact of ESCA-associated chemokines and their receptors on ESCA, emphasizing their critical involvement in the ESCA TME.
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Affiliation(s)
| | - Zhiqiang Sun
- Department of Radiation Oncology, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou, China
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Korbecki J, Bosiacki M, Stasiak P, Snarski E, Brodowska A, Chlubek D, Baranowska-Bosiacka I. Clinical Aspects and Significance of β-Chemokines, γ-Chemokines, and δ-Chemokines in Molecular Cancer Processes in Acute Myeloid Leukemia (AML) and Myelodysplastic Neoplasms (MDS). Cancers (Basel) 2024; 16:3246. [PMID: 39409868 PMCID: PMC11476337 DOI: 10.3390/cancers16193246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 09/15/2024] [Accepted: 09/20/2024] [Indexed: 10/20/2024] Open
Abstract
BACKGROUND/OBJECTIVES Acute myeloid leukemia (AML) is a type of leukemia with a very poor prognosis. Consequently, this neoplasm is extensively researched to discover new therapeutic strategies. One area of investigation is the study of intracellular communication and the impact of the bone marrow microenvironment on AML cells, with chemokines being a key focus. The roles of β-chemokines, γ-chemokines, and δ-chemokines in AML processes have not yet been sufficiently characterized. METHODS This publication summarizes all available knowledge about these chemotactic cytokines in AML and myelodysplastic neoplasm (MDS) processes and presents potential therapeutic strategies to combat the disease. The significance of β-chemokines, γ-chemokines, and δ-chemokines is detailed, including CCL2 (MCP-1), CCL3 (MIP-1α), CCL5 (RANTES), CCL23, CCL28, and CX3CL1 (fractalkine). Additionally, the importance of atypical chemokine receptors in AML is discussed, specifically ACKR1, ACKR2, ACKR4, and CCRL2. RESULTS/CONCLUSIONS The focus is on the effects of these chemokines on AML cells, particularly their influence on proliferation and resistance to anti-leukemic drugs. Intercellular interactions with non-AML cells, such as mesenchymal stem cells (MSC), macrophages, and regulatory T cells (Treg), are also characterized. The clinical aspects of chemokines are thoroughly explained, including their effect on overall survival and the relationship between their blood levels and AML characteristics.
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Affiliation(s)
- Jan Korbecki
- Department of Anatomy and Histology, Collegium Medicum, University of Zielona Góra, Zyty 28, 65-046 Zielona Góra, Poland; (J.K.); (P.S.)
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (M.B.)
| | - Mateusz Bosiacki
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (M.B.)
| | - Piotr Stasiak
- Department of Anatomy and Histology, Collegium Medicum, University of Zielona Góra, Zyty 28, 65-046 Zielona Góra, Poland; (J.K.); (P.S.)
| | - Emilian Snarski
- Institute of Medical Sciences, Collegium Medicum, University of Zielona Góra, Zyty 28 Str., 65-046 Zielona Góra, Poland;
| | - Agnieszka Brodowska
- Department of Gynecology, Endocrinology and Gynecological Oncology, Pomeranian Medical University in Szczecin, Unii Lubelskiej 1, 71-252 Szczecin, Poland;
| | - Dariusz Chlubek
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (M.B.)
| | - Irena Baranowska-Bosiacka
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (M.B.)
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Huang CG, Liu Q, Zheng ST, Liu T, Tan YY, Peng TY, Chen J, Lu XM. Chemokines and Their Receptors: Predictors of Therapeutic Potential in Tumor Microenvironment on Esophageal Cancer. Dig Dis Sci 2024; 69:1562-1570. [PMID: 38580886 PMCID: PMC11098888 DOI: 10.1007/s10620-024-08392-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 03/14/2024] [Indexed: 04/07/2024]
Abstract
Esophageal carcinoma (ESCA) is an aggressive solid tumor. The 5-year survival rate for patients with ESCA is estimated to be less than 20%, mainly due to tumor invasion and metastasis. Therefore, it is urgent to improve early diagnostic tools and effective treatments for ESCA patients. Tumor microenvironment (TME) enhances the ability of tumor cells to proliferate, migrate, and escape from the immune system, thus promoting the occurrence and development of tumor. TME contains chemokines. Chemokines consist of four major families, which are mainly composed of CC and CXC families. The main purpose of this review is to understand the CC and CXC chemokines and their receptors in ESCA, to improve the understanding of tumorigenesis of ESCA and determine new biomarkers for the diagnosis and prognosis of ESCA. We reviewed the literature on CC and CXC chemokines and their receptors in ESCA identified by PubMed database. This article introduces the general structures and functions of CC, CXC chemokines and their receptors in TME, as well as their roles in the progress of ESCA. Chemokines are involved in the development of ESCA, such as cancer cell invasion, metastasis, angiogenesis, and radioresistance, and are key determinants of disease progression, which have a great impact on patient prognosis and treatment response. In addition, a full understanding of their mechanism of action is essential to further verify that these chemokines and their receptors may serve as biomarkers or therapeutic targets of ESCA.
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Affiliation(s)
- Cong-Gai Huang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region, China
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, People's Republic of China
- Precision Pathology Diagnosis for Serious Diseases Key Laboratory of Luzhou, Luzhou, People's Republic of China
| | - Qing Liu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Shu-Tao Zheng
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Tao Liu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Yi-Yi Tan
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Tian-Yuan Peng
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Jiao Chen
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Xiao-Mei Lu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region, China.
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Cross AL, Hawkes J, Frankland H, Mediana A, Wright HL, Goodson NJ, Edwards SW, Moots RJ. Neutrophil function following treatment of psoriatic arthritis patients with secukinumab: altered cytokine signalling but no impairment of host defence. Rheumatology (Oxford) 2023; 62:3025-3034. [PMID: 36617171 DOI: 10.1093/rheumatology/kead007] [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: 07/12/2022] [Revised: 10/25/2022] [Accepted: 11/01/2022] [Indexed: 01/09/2023] Open
Abstract
OBJECTIVES Identifying that dysfunction of the IL-23/17 axis underlies PsA has led to the development of effective targeted therapies such as the IL-17A inhibitor secukinumab. As IL-17A stimulates the secretion of neutrophil chemoattractants, such as CXCL8 (IL-8), we examined the effect of secukinumab on neutrophil function in PsA. METHODS Nineteen patients with active PsA were treated with secukinumab. Clinical response [PsA Response Criteria (PsARC) and Psoriasis Area and Severity Index (PASI)] and peripheral blood neutrophil function (apoptosis, receptor expression, phagocytosis/killing, chemotaxis and RNA expression) were measured at 12 week intervals for 48 weeks and compared with age- and sex-matched healthy controls. RESULTS At 12 weeks, 12/16 (75%) patients had a PsARC response (100% at 36 weeks) and 10/14 (71%) achieved a 90% PASI response. At baseline, there were no differences in PsA neutrophil reactive oxygen species generation, constitutive or cytokine-delayed apoptosis, chemotaxis or phagocytosis of opsonized Staphylococcus aureus compared with healthy controls. Similarly, there were no differences in these functions from baseline to 12 weeks of therapy. However, surface levels of CD11b/CD18 and CD63 increased and expression of CD16 decreased during therapy. In addition, in a subgroup of early (12 week) responders to secukinumab, RNA sequencing revealed transcriptome changes predicting down-regulation of cytokine signalling and chemotaxis pathways and up-regulation of de novo gene expression pathways, including translation initiation, mRNA catabolism and translation. CONCLUSION Complex changes in the properties of circulating neutrophils occur with secukinumab treatment in PsA that may indicate altered responsiveness to changes in both local and systemic levels of pro-inflammatory cytokines. However, host defence processes of neutrophils were unaltered.
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Affiliation(s)
- Andrew L Cross
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Jenny Hawkes
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Helen Frankland
- Department of Rheumatology, Aintree University Hospital, Liverpool, UK
| | - Ayren Mediana
- Department of Rheumatology, Aintree University Hospital, Liverpool, UK
| | - Helen L Wright
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Nicola J Goodson
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Steven W Edwards
- Institute of Infection, Veterinary and Ecological Sciences, Liverpool, UK
| | - Robert J Moots
- Department of Rheumatology, Aintree University Hospital, Liverpool, UK
- Faculty of Health, Social Care and Medicine, Edge Hill University, Ormskirk, UK
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Li R, Huang B, Tian H, Sun Z. Immune evasion in esophageal squamous cell cancer: From the perspective of tumor microenvironment. Front Oncol 2023; 12:1096717. [PMID: 36698392 PMCID: PMC9868934 DOI: 10.3389/fonc.2022.1096717] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 12/19/2022] [Indexed: 01/12/2023] Open
Abstract
Esophageal cancer (EC) is one of the most life-threatening malignancies worldwide. Esophageal squamous cell carcinoma (ESCC) is the dominant subtype, accounting for approximately 90% of new incident EC each year. Although multidisciplinary treatment strategies have advanced rapidly, patients with ESCC are often diagnosed at advanced stage and the long-term prognosis remains unsatisfactory. In recent decades, immunotherapy, such as immune checkpoint inhibitors (ICIs), tumor vaccines, and chimeric antigen receptor T-cell (CAR-T) therapy, has been successfully used in clinical practice as a novel therapy for treating tumors, bringing new hope to ESCC patients. However, only a small fraction of patients achieved clinical benefits due to primary or acquired resistance. Immune evasion plays a pivotal role in the initiation and progression of ESCC. Therefore, a thorough understanding of the mechanisms by which ESCC cells escape from anti-tumor immunity is necessary for a more effective multidisciplinary treatment strategy. It has been widely recognized that immune evasion is closely associated with the crosstalk between tumor cells and the tumor microenvironment (TME). TME is a dynamic complex and comprehensive system including not only cellular components but also non-cellular components, which influence hallmarks and fates of tumor cells from the outside. Novel immunotherapy targeting tumor-favorable TME represents a promising strategy to achieve better therapeutic responses for patients with ESCC. In this review, we provide an overview of immune evasion in ESCC, mainly focusing on the molecular mechanisms that underlie the role of TME in immune evasion of ESCC. In addition, we also discuss the challenges and opportunities of precision therapy for ESCC by targeting TME.
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Affiliation(s)
| | | | | | - Zhenguo Sun
- Department of Thoracic Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
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Iraji D, Oftedal BE, Wolff ASB. Th17 Cells: Orchestrators of Mucosal Inflammation and Potential Therapeutic Targets. Crit Rev Immunol 2023; 43:25-52. [PMID: 37831521 DOI: 10.1615/critrevimmunol.2023050360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2023]
Abstract
T helper 17 (Th17) cells represent a specialized subgroup of effector CD4+ T cells known for their role in provoking neutrophil-driven tissue inflammation, particularly within mucosal tissues. Although they are pivotal for defending the host against extracellular bacteria and fungi, they have also been associated with development of various T cell-mediated inflammatory conditions, autoimmune diseases, and even cancer. Notably, Th17 cells exhibit a dual nature, with different Th17 cell subtypes showcasing distinct effector functions and varying capacities to incite autoimmune tissue inflammation. Furthermore, Th17 cells exhibit significant plasticity, which carries important functional implications, both in terms of their expression of cytokines typically associated with other effector T cell subsets and in their interactions with regulatory CD4+ T cells. The intricate balance of Th17 cytokines can also be a double-edged sword in inflammation, autoimmunity, and cancer. Within this article, we delve into the mechanisms that govern the differentiation, function, and adaptability of Th17 cells. We culminate with an exploration of therapeutic potentials in harnessing the power of Th17 cells and their cytokines. Targeted interventions to modulate Th17 responses are emerging as promising strategies for autoimmunity, inflammation, and cancer treatment. By precisely fine-tuning Th17-related pathways, we may unlock new avenues for personalized therapeutic approaches, aiming to restore immune balance, alleviate the challenges of these disorders, and ultimately enhance the quality of life for individuals affected by them.
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Affiliation(s)
- Dorsa Iraji
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Bergithe E Oftedal
- Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Anette S B Wolff
- Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Medicine, Haukeland University Hospital, Bergen, Norway
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8
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Asano T, Tanaka T, Suzuki H, Li G, Nanamiya R, Tateyama N, Isoda Y, Okada Y, Kobayashi H, Yoshikawa T, Kaneko MK, Kato Y. Development of a Novel Anti-Mouse CCR6 Monoclonal Antibody (C 6Mab-13) by N-Terminal Peptide Immunization. Monoclon Antib Immunodiagn Immunother 2022; 41:343-349. [PMID: 36383115 DOI: 10.1089/mab.2022.0021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The CC chemokine receptor 6 (CCR6) is a G protein-coupled receptor family member that is highly expressed in B lymphocytes, certain subsets of effector and memory T cells, and immature dendritic cells. CCR6 has only one chemokine ligand, CCL20. The CCL20-CCR6 axis has been recognized as a therapeutic target for autoimmune diseases and tumor. This study developed specific monoclonal antibodies (mAbs) against mouse CCR6 (mCCR6) using the peptide immunization method. The established anti-mCCR6 mAb, C6Mab-13 (rat IgG1, kappa), reacted with mCCR6-overexpressed Chinese hamster ovary-K1 (CHO/mCCR6), and mCCR6-endogenously expressed P388 (mouse lymphoid neoplasma) and J774-1 (mouse macrophage-like) cells in flow cytometry. The dissociation constant (KD) of C6Mab-13 for CHO/mCCR6 cells was determined to be 2.8 × 10-9 M, indicating that C6Mab-13 binds to mCCR6 with high affinity. In summary, C6Mab-13 is useful for detecting mCCR6-expressing cells through flow cytometry.
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Affiliation(s)
- Teizo Asano
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Tomohiro Tanaka
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Hiroyuki Suzuki
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Guanjie Li
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Ren Nanamiya
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Nami Tateyama
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Yu Isoda
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Yuki Okada
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Hiyori Kobayashi
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Takeo Yoshikawa
- Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Mika K Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Yukinari Kato
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.,Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.,Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
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Zheng S, Liu B, Guan X. The Role of Tumor Microenvironment in Invasion and Metastasis of Esophageal Squamous Cell Carcinoma. Front Oncol 2022; 12:911285. [PMID: 35814365 PMCID: PMC9257257 DOI: 10.3389/fonc.2022.911285] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 05/18/2022] [Indexed: 12/24/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in the world, with a high rate of morbidity. The invasion and metastasis of ESCC is the main reason for high mortality. More and more evidence suggests that metastasized cancer cells require cellular elements that contribute to ESCC tumor microenvironment (TME) formation. TME contains many immune cells and stromal components, which are critical to epithelial–mesenchymal transition, immune escape, angiogenesis/lymphangiogenesis, metastasis niche formation, and invasion/metastasis. In this review, we will focus on the mechanism of different microenvironment cellular elements in ESCC invasion and metastasis and discuss recent therapeutic attempts to restore the tumor-suppressing function of cells within the TME. It will represent the whole picture of TME in the metastasis and invasion process of ESCC.
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Affiliation(s)
- Shuyue Zheng
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Beilei Liu
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Xinyuan Guan
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, China
- *Correspondence: Xinyuan Guan,
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Mahhengam N, Kazemnezhad K, Setia Budi H, Ansari MJ, Olegovich Bokov D, Suksatan W, Thangavelu L, Siahmansouri H. Targeted therapy of tumor microenvironment by gold nanoparticles as a new therapeutic approach. J Drug Target 2022; 30:494-510. [DOI: 10.1080/1061186x.2022.2032095] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Negah Mahhengam
- Faculty of General Medicine, Belarusian State Medical University, Minsk, Belarus.
| | - Kimia Kazemnezhad
- Faculty of General Medicine, Belarusian State Medical University, Minsk, Belarus.
| | - Hendrik Setia Budi
- Department of Oral Biology, Faculty of Dental Medicine, Universitas Airlangga, Surabaya 60132, Indonesia.
| | - Mohammad Javed Ansari
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University,Al-kharj, Saudi Arabia.
| | - Dmitry Olegovich Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., bldg. 2, Moscow, 119991, Russian Federation.
| | - Wanich Suksatan
- Faculty of Nursing, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand.
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai, India.
| | - Homayoon Siahmansouri
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Multifaceted Roles of Chemokines and Chemokine Receptors in Tumor Immunity. Cancers (Basel) 2021; 13:cancers13236132. [PMID: 34885241 PMCID: PMC8656932 DOI: 10.3390/cancers13236132] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/26/2021] [Accepted: 12/02/2021] [Indexed: 12/22/2022] Open
Abstract
Simple Summary Various immune cells are involved in host immune responses to cancer. T-helper (Th) 1 cells, cytotoxic CD8+ T cells, and natural killer cells are the major effector cells in anti-tumor immunity, whereas cells such as regulatory T cells and myeloid-derived suppressor cells are negatively involved in anti-tumor immunity. Th2 cells and Th17 cells have been shown to have both pro-tumor and anti-tumor activities. The migratory properties of various immune cells are essential for their function and critically regulated by the chemokine superfamily. In this review, we summarize the roles of various immune cells in tumor immunity and their migratory regulation by the chemokine superfamily. We also assess the therapeutic possibilities of targeting chemokines and chemokine receptors in cancer immunotherapy. Abstract Various immune cells are involved in host tumor immune responses. In particular, there are many T cell subsets with different roles in tumor immunity. T-helper (Th) 1 cells are involved in cellular immunity and thus play the major role in host anti-tumor immunity by inducing and activating cytotoxic T lymphocytes (CTLs). On the other hand, Th2 cells are involved in humoral immunity and suppressive to Th1 responses. Regulatory T (Treg) cells negatively regulate immune responses and contribute to immune evasion of tumor cells. Th17 cells are involved in inflammatory responses and may play a role in tumor progression. However, recent studies have also shown that Th17 cells are capable of directly inducting CTLs and thus may promote anti-tumor immunity. Besides these T cell subsets, there are many other innate immune cells such as dendritic cells (DCs), natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs) that are involved in host immune responses to cancer. The migratory properties of various immune cells are critical for their functions and largely regulated by the chemokine superfamily. Thus, chemokines and chemokine receptors play vital roles in the orchestration of host immune responses to cancer. In this review, we overview the various immune cells involved in host responses to cancer and their migratory properties regulated by the chemokine superfamily. Understanding the roles of chemokines and chemokine receptors in host immune responses to cancer may provide new therapeutic opportunities for cancer immunotherapy.
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Marques HS, de Brito BB, da Silva FAF, Santos MLC, de Souza JCB, Correia TML, Lopes LW, Neres NSDM, Dórea RSDM, Dantas ACS, Morbeck LLB, Lima IS, de Almeida AA, Dias MRDJ, de Melo FF. Relationship between Th17 immune response and cancer. World J Clin Oncol 2021; 12:845-867. [PMID: 34733609 PMCID: PMC8546660 DOI: 10.5306/wjco.v12.i10.845] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 07/21/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
Cancer is the second leading cause of death worldwide and epidemiological projections predict growing cancer mortality rates in the next decades. Cancer has a close relationship with the immune system and, although Th17 cells are known to play roles in the immune response against microorganisms and in autoimmunity, studies have emphasized their roles in cancer pathogenesis. The Th17 immune response profile is involved in several types of cancer including urogenital, respiratory, gastrointestinal, and skin cancers. This type of immune response exerts pro and antitumor functions through several mechanisms, depending on the context of each tumor, including the protumor angiogenesis and exhaustion of T cells and the antitumor recruitment of T cells and neutrophils to the tumor microenvironment. Among other factors, the paradoxical behavior of Th17 cells in this setting has been attributed to its plasticity potential, which makes possible their conversion into other types of T cells such as Th17/Treg and Th17/Th1 cells. Interleukin (IL)-17 stands out among Th17-related cytokines since it modulates pathways and interacts with other cell profiles in the tumor microenvironment, which allow Th17 cells to prevail in tumors. Moreover, the IL-17 is able to mediate pro and antitumor processes that influence the development and progression of various cancers, being associated with variable clinical outcomes. The understanding of the relationship between the Th17 immune response and cancer as well as the singularities of carcinogenic processes in each type of tumor is crucial for the identification of new therapeutic targets.
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Affiliation(s)
- Hanna Santos Marques
- Campus Vitória da Conquista, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista 45083-900, Bahia, Brazil
| | - Breno Bittencourt de Brito
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Maria Luísa Cordeiro Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Júlio César Braga de Souza
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Thiago Macêdo Lopes Correia
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Luana Weber Lopes
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Nayara Silva de Macêdo Neres
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Anna Carolina Saúde Dantas
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Lorena Lôbo Brito Morbeck
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Iasmin Souza Lima
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Amanda Alves de Almeida
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Maiara Raulina de Jesus Dias
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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Mukherjee N, Ji N, Tan X, Lin C, Rios E, Chen C, Huang T, Svatek RS. Bladder tumor ILC1s undergo Th17-like differentiation in human bladder cancer. Cancer Med 2021; 10:7101-7110. [PMID: 34496133 PMCID: PMC8525153 DOI: 10.1002/cam4.4243] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 07/19/2021] [Accepted: 07/20/2021] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Human innate lymphoid cells (hILCs) are lineage-negative immune cells that do not express rearranged adaptive antigen receptors. Natural killer (NK) cells are hILCs that contribute to cancer defense. The role of non-NK hILCs in cancer is unclear. Our study aimed to characterize non-NK hILCs in bladder cancer. EXPERIMENTAL DESIGN Mass cytometry was used to characterize intratumoral non-NK hILCs based on 35 parameters, including receptors, cytokines, and transcription factors from 21 muscle-invasive bladder tumors. Model-based clustering was performed on t-distributed stochastic neighbor embedding (t-SNE) coordinates of hILCs, and the association of hILCs with tumor stage was analyzed. RESULTS Most frequent among intratumoral non-NK hILCs were hILC1s, which were increased in higher compared with lower stage tumors. Intratumoral hILC1s were marked by Th17-like phenotype with high RORγt, IL-17, and IL-22 compared to Th1 differentiation markers, including Tbet, perforin, and IFN-γ. Compared with intratumoral hILC2s and hILC3s, hILC1s also had lower expression of activation markers (NKp30, NKp46, and CD69) and increased expression of exhaustion molecules (PD-1 and Tim3). Unsupervised clustering identified nine clusters of bladder hILCs, which were not defined by the primary hILC subtypes 1-3. hILC1s featured in all the nine clusters indicating that intratumoral hILC1s displayed the highest phenotypic heterogeneity among all hILCs. CONCLUSIONS hILC1s are increased in higher stage tumors among patients with muscle-invasive bladder cancer. These intratumoral hILC1s exhibit an exhausted phenotype and Th17-like differentiation, identifying them as potential targets for immunotherapy.
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Affiliation(s)
- Neelam Mukherjee
- Department of UrologyUniversity of Texas Health San Antonio (UTHSA)San AntonioTexasUSA
| | - Niannian Ji
- Department of UrologyUniversity of Texas Health San Antonio (UTHSA)San AntonioTexasUSA
| | - Xi Tan
- Department of Molecular MedicineUniversity of Texas Health San Antonio (UTHSA)San AntonioTexasUSA
| | - Chun‐Lin Lin
- Department of Molecular MedicineUniversity of Texas Health San Antonio (UTHSA)San AntonioTexasUSA
| | - Emily Rios
- Department of UrologyUniversity of Texas Health San Antonio (UTHSA)San AntonioTexasUSA
| | - Chun‐Liang Chen
- Department of Molecular MedicineUniversity of Texas Health San Antonio (UTHSA)San AntonioTexasUSA
| | - Tim Huang
- Department of Molecular MedicineUniversity of Texas Health San Antonio (UTHSA)San AntonioTexasUSA
| | - Robert S. Svatek
- Department of UrologyUniversity of Texas Health San Antonio (UTHSA)San AntonioTexasUSA
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O'Donovan C, Davern M, Donlon NE, Lysaght J, Conroy MJ. Chemokine-targeted therapies: An opportunity to remodel immune profiles in gastro-oesophageal tumours. Cancer Lett 2021; 521:224-236. [PMID: 34506844 DOI: 10.1016/j.canlet.2021.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/18/2021] [Accepted: 09/05/2021] [Indexed: 02/07/2023]
Abstract
Immunotherapies are transforming outcomes for many cancer patients and are quickly becoming the fourth pillar of cancer therapy. However, their efficacy of only ∼25% in gastro-oesophageal cancer has been disappointing. This is attributed to factors such as insufficient patient stratification and the pro-tumourigenic immune landscape of gastro-oesophageal tumours. The chemokine profiles of solid tumours and the availability of effector immune cells greatly influence the immune infiltrate, producing 'cold' or 'immune-excluded' tumours in which immunotherapies are unable to reinvigorate the immune response. Other biological functions for chemokines have emerged, such as promoting cell survival, polarising T cell responses, and supporting several hallmarks of cancer. Therefore, chemokine networks may be exploited with therapeutic intent to mobilise and polarise anti-tumour immune cells, with further utility as combination treatments to augment the efficacy of current cancer immunotherapies. Few studies have demonstrated the clinical benefit of chemokine-targeted therapies as monotherapies, and this review proposes their consideration as combination treatments. Herein, we explore the anti-tumour and pro-tumour implications of chemokine signalling in gastro-oesophageal cancer and discuss their value as prognostic and predictive biomarkers in response to treatment.
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Affiliation(s)
- Cillian O'Donovan
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital Campus, Dublin 8, Ireland
| | - Maria Davern
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital Campus, Dublin 8, Ireland
| | - Noel E Donlon
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital Campus, Dublin 8, Ireland
| | - Joanne Lysaght
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital Campus, Dublin 8, Ireland
| | - Melissa J Conroy
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital Campus, Dublin 8, Ireland; Department of Physiology, School of Medicine, Trinity College, Dublin, Ireland.
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Recruitment and Expansion of Tregs Cells in the Tumor Environment-How to Target Them? Cancers (Basel) 2021; 13:cancers13081850. [PMID: 33924428 PMCID: PMC8069615 DOI: 10.3390/cancers13081850] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/04/2021] [Accepted: 04/08/2021] [Indexed: 12/22/2022] Open
Abstract
Simple Summary The immune response against cancer is generated by effector T cells, among them cytotoxic CD8+ T cells that destroy cancer cells and helper CD4+ T cells that mediate and support the immune response. This antitumor function of T cells is tightly regulated by a particular subset of CD4+ T cells, named regulatory T cells (Tregs), through different mechanisms. Even if the complete inhibition of Tregs would be extremely harmful due to their tolerogenic role in impeding autoimmune diseases in the periphery, the targeted blockade of their accumulation at tumor sites or their targeted depletion represent a major therapeutic challenge. This review focuses on the mechanisms favoring Treg recruitment, expansion and stabilization in the tumor microenvironment and the therapeutic strategies developed to block these mechanisms. Abstract Regulatory T cells (Tregs) are present in a large majority of solid tumors and are mainly associated with a poor prognosis, as their major function is to inhibit the antitumor immune response contributing to immunosuppression. In this review, we will investigate the mechanisms involved in the recruitment, amplification and stability of Tregs in the tumor microenvironment (TME). We will also review the strategies currently developed to inhibit Tregs’ deleterious impact in the TME by either inhibiting their recruitment, blocking their expansion, favoring their plastic transformation into other CD4+ T-cell subsets, blocking their suppressive function or depleting them specifically in the TME to avoid severe deleterious effects associated with Treg neutralization/depletion in the periphery and normal tissues.
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Heeran AB, Dunne MR, Morrissey ME, Buckley CE, Clarke N, Cannon A, Donlon NE, Nugent TS, Durand M, Dunne C, Larkin JO, Mehigan B, McCormick P, Lynam-Lennon N, O’Sullivan J. The Protein Secretome Is Altered in Rectal Cancer Tissue Compared to Normal Rectal Tissue, and Alterations in the Secretome Induce Enhanced Innate Immune Responses. Cancers (Basel) 2021; 13:571. [PMID: 33540635 PMCID: PMC7867296 DOI: 10.3390/cancers13030571] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 01/25/2021] [Indexed: 02/07/2023] Open
Abstract
Locally advanced rectal cancer is treated with neoadjuvant-chemoradiotherapy; however, only ~22% of patients achieve a complete response, and resistance mechanisms are poorly understood. The role of inflammation and immune cell biology in this setting is under-investigated. In this study, we profiled the inflammatory protein secretome of normal (non-cancer) (n = 8) and malignant rectal tissue (n = 12) pre- and post-radiation in human ex vivo explant models and examined the influence of these untreated and treated secretomes on dendritic cell biology (n = 8 for cancer and normal). These resultant profiles were correlated with patient clinical characteristics. Nineteen factors were secreted at significantly higher levels from the rectal cancer secretome when compared to the normal rectal secretome; Flt-1, P1GF, IFN-γ, IL-6, IL-10, CCL20, CCL26, CCL22, CCL3, CCL4, CCL17, GM-CSF, IL-12/IL-23p40, IL-17A, IL-1α, IL-17A/F, IL-1RA, TSLP and CXCL10 (p < 0.05). Radiation was found to have differential effects on normal rectal tissue and rectal cancer tissue with increased IL-15 and CCL22 secretion following radiation from normal rectal tissue explants (p < 0.05), while no significant alterations were observed in the irradiated rectal cancer tissue. Interestingly, however, the irradiated rectal cancer secretome induced the most potent effect on dendritic cell maturation via upregulation of CD80 and PD-L1. Patient's visceral fat area correlated with secreted factors including CCL20, suggesting that obesity status may alter the tumour microenvironment (TME). These results suggest that radiation does not have a negative effect on the ability of the rectal cancer TME to induce an immune response. Understanding these responses may unveil potential therapeutic targets to enhance radiation response and mitigate normal tissue injury. Tumour irradiation in this cohort enhances innate immune responses, which may be harnessed to improve patient treatment outcome.
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Affiliation(s)
- Aisling B. Heeran
- Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin and St. James’s Hospital, D08 W9RT Dublin 8, Ireland; (A.B.H.); (M.R.D.); (M.E.M.); (C.E.B.); (N.C.); (A.C.); (N.E.D.); (T.S.N.); (N.L.-L.)
| | - Margaret R. Dunne
- Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin and St. James’s Hospital, D08 W9RT Dublin 8, Ireland; (A.B.H.); (M.R.D.); (M.E.M.); (C.E.B.); (N.C.); (A.C.); (N.E.D.); (T.S.N.); (N.L.-L.)
| | - Maria E. Morrissey
- Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin and St. James’s Hospital, D08 W9RT Dublin 8, Ireland; (A.B.H.); (M.R.D.); (M.E.M.); (C.E.B.); (N.C.); (A.C.); (N.E.D.); (T.S.N.); (N.L.-L.)
| | - Croí E. Buckley
- Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin and St. James’s Hospital, D08 W9RT Dublin 8, Ireland; (A.B.H.); (M.R.D.); (M.E.M.); (C.E.B.); (N.C.); (A.C.); (N.E.D.); (T.S.N.); (N.L.-L.)
| | - Niamh Clarke
- Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin and St. James’s Hospital, D08 W9RT Dublin 8, Ireland; (A.B.H.); (M.R.D.); (M.E.M.); (C.E.B.); (N.C.); (A.C.); (N.E.D.); (T.S.N.); (N.L.-L.)
| | - Aoife Cannon
- Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin and St. James’s Hospital, D08 W9RT Dublin 8, Ireland; (A.B.H.); (M.R.D.); (M.E.M.); (C.E.B.); (N.C.); (A.C.); (N.E.D.); (T.S.N.); (N.L.-L.)
| | - Noel E. Donlon
- Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin and St. James’s Hospital, D08 W9RT Dublin 8, Ireland; (A.B.H.); (M.R.D.); (M.E.M.); (C.E.B.); (N.C.); (A.C.); (N.E.D.); (T.S.N.); (N.L.-L.)
| | - Timothy S. Nugent
- Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin and St. James’s Hospital, D08 W9RT Dublin 8, Ireland; (A.B.H.); (M.R.D.); (M.E.M.); (C.E.B.); (N.C.); (A.C.); (N.E.D.); (T.S.N.); (N.L.-L.)
| | - Michael Durand
- GEMS, St. James’s Hospital, D08 NHY1 Dublin 8, Ireland; (M.D.); (C.D.); (J.O.L.); (B.M.); (P.M.)
| | - Cara Dunne
- GEMS, St. James’s Hospital, D08 NHY1 Dublin 8, Ireland; (M.D.); (C.D.); (J.O.L.); (B.M.); (P.M.)
| | - John O. Larkin
- GEMS, St. James’s Hospital, D08 NHY1 Dublin 8, Ireland; (M.D.); (C.D.); (J.O.L.); (B.M.); (P.M.)
| | - Brian Mehigan
- GEMS, St. James’s Hospital, D08 NHY1 Dublin 8, Ireland; (M.D.); (C.D.); (J.O.L.); (B.M.); (P.M.)
| | - Paul McCormick
- GEMS, St. James’s Hospital, D08 NHY1 Dublin 8, Ireland; (M.D.); (C.D.); (J.O.L.); (B.M.); (P.M.)
| | - Niamh Lynam-Lennon
- Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin and St. James’s Hospital, D08 W9RT Dublin 8, Ireland; (A.B.H.); (M.R.D.); (M.E.M.); (C.E.B.); (N.C.); (A.C.); (N.E.D.); (T.S.N.); (N.L.-L.)
| | - Jacintha O’Sullivan
- Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin and St. James’s Hospital, D08 W9RT Dublin 8, Ireland; (A.B.H.); (M.R.D.); (M.E.M.); (C.E.B.); (N.C.); (A.C.); (N.E.D.); (T.S.N.); (N.L.-L.)
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CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of the Ligands of Receptors CCR1, CCR2, CCR3, and CCR4. Int J Mol Sci 2020; 21:ijms21218412. [PMID: 33182504 PMCID: PMC7665155 DOI: 10.3390/ijms21218412] [Citation(s) in RCA: 227] [Impact Index Per Article: 45.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 11/06/2020] [Accepted: 11/08/2020] [Indexed: 12/14/2022] Open
Abstract
CC chemokines, a subfamily of 27 chemotactic cytokines, are a component of intercellular communication, which is crucial for the functioning of the tumor microenvironment. Although many individual chemokines have been well researched, there has been no comprehensive review presenting the role of all known human CC chemokines in the hallmarks of cancer, and this paper aims at filling this gap. The first part of this review discusses the importance of CCL1, CCL3, CCL4, CCL5, CCL18, CCL19, CCL20, CCL21, CCL25, CCL27, and CCL28 in cancer. Here, we discuss the significance of CCL2 (MCP-1), CCL7, CCL8, CCL11, CCL13, CCL14, CCL15, CCL16, CCL17, CCL22, CCL23, CCL24, and CCL26. The presentation of each chemokine includes its physiological function and then the role in tumor, including proliferation, drug resistance, migration, invasion, and organ-specific metastasis of tumor cells, as well as the effects on angiogenesis and lymphangiogenesis. We also discuss the effects of each CC chemokine on the recruitment of cancer-associated cells to the tumor niche (eosinophils, myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM), tumor-associated neutrophils (TAN), regulatory T cells (Treg)). On the other hand, we also present the anti-cancer properties of CC chemokines, consisting in the recruitment of tumor-infiltrating lymphocytes (TIL).
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Korbecki J, Grochans S, Gutowska I, Barczak K, Baranowska-Bosiacka I. CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands. Int J Mol Sci 2020; 21:ijms21207619. [PMID: 33076281 PMCID: PMC7590012 DOI: 10.3390/ijms21207619] [Citation(s) in RCA: 237] [Impact Index Per Article: 47.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/05/2020] [Accepted: 10/13/2020] [Indexed: 02/07/2023] Open
Abstract
CC chemokines (or β-chemokines) are 28 chemotactic cytokines with an N-terminal CC domain that play an important role in immune system cells, such as CD4+ and CD8+ lymphocytes, dendritic cells, eosinophils, macrophages, monocytes, and NK cells, as well in neoplasia. In this review, we discuss human CC motif chemokine ligands: CCL1, CCL3, CCL4, CCL5, CCL18, CCL19, CCL20, CCL21, CCL25, CCL27, and CCL28 (CC motif chemokine receptor CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 ligands). We present their functioning in human physiology and in neoplasia, including their role in the proliferation, apoptosis resistance, drug resistance, migration, and invasion of cancer cells. We discuss the significance of chemokine receptors in organ-specific metastasis, as well as the influence of each chemokine on the recruitment of various cells to the tumor niche, such as cancer-associated fibroblasts (CAF), Kupffer cells, myeloid-derived suppressor cells (MDSC), osteoclasts, tumor-associated macrophages (TAM), tumor-infiltrating lymphocytes (TIL), and regulatory T cells (Treg). Finally, we show how the effect of the chemokines on vascular endothelial cells and lymphatic endothelial cells leads to angiogenesis and lymphangiogenesis.
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Affiliation(s)
- Jan Korbecki
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72 Av., 70-111 Szczecin, Poland; (J.K.); (S.G.)
| | - Szymon Grochans
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72 Av., 70-111 Szczecin, Poland; (J.K.); (S.G.)
| | - Izabela Gutowska
- Department of Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72 Av., 70-111 Szczecin, Poland;
| | - Katarzyna Barczak
- Department of Conservative Dentistry and Endodontics, Pomeranian Medical University, Powstańców Wlkp. 72 Av., 70-111 Szczecin, Poland;
| | - Irena Baranowska-Bosiacka
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72 Av., 70-111 Szczecin, Poland; (J.K.); (S.G.)
- Correspondence: ; Tel.: +48-914661515
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Korbecki J, Kojder K, Barczak K, Simińska D, Gutowska I, Chlubek D, Baranowska-Bosiacka I. Hypoxia Alters the Expression of CC Chemokines and CC Chemokine Receptors in a Tumor-A Literature Review. Int J Mol Sci 2020; 21:ijms21165647. [PMID: 32781743 PMCID: PMC7460668 DOI: 10.3390/ijms21165647] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/03/2020] [Accepted: 08/04/2020] [Indexed: 02/06/2023] Open
Abstract
Hypoxia, i.e., oxygen deficiency condition, is one of the most important factors promoting the growth of tumors. Since its effect on the chemokine system is crucial in understanding the changes in the recruitment of cells to a tumor niche, in this review we have gathered all the available data about the impact of hypoxia on β chemokines. In the introduction, we present the chronic (continuous, non-interrupted) and cycling (intermittent, transient) hypoxia together with the mechanisms of activation of hypoxia inducible factors (HIF-1 and HIF-2) and NF-κB. Then we describe the effect of hypoxia on the expression of chemokines with the CC motif: CCL1, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL13, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL24, CCL25, CCL26, CCL27, CCL28 together with CC chemokine receptors: CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10. To better understand the effect of hypoxia on neoplastic processes and changes in the expression of the described proteins, we summarize the available data in a table which shows the effect of individual chemokines on angiogenesis, lymphangiogenesis, and recruitment of eosinophils, myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg), and tumor-associated macrophages (TAM) to a tumor niche.
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Affiliation(s)
- Jan Korbecki
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland; (J.K.); (D.S.); (D.C.)
| | - Klaudyna Kojder
- Department of Anaesthesiology and Intensive Care, Pomeranian Medical University in Szczecin, Unii Lubelskiej 1, 71-281 Szczecin, Poland;
| | - Katarzyna Barczak
- Department of Conservative Dentistry and Endodontics, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland;
| | - Donata Simińska
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland; (J.K.); (D.S.); (D.C.)
| | - Izabela Gutowska
- Department of Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland;
| | - Dariusz Chlubek
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland; (J.K.); (D.S.); (D.C.)
| | - Irena Baranowska-Bosiacka
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland; (J.K.); (D.S.); (D.C.)
- Correspondence: ; Tel.: +48-914661515; Fax: +48-914661516
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Kadomoto S, Izumi K, Mizokami A. The CCL20-CCR6 Axis in Cancer Progression. Int J Mol Sci 2020; 21:ijms21155186. [PMID: 32707869 PMCID: PMC7432448 DOI: 10.3390/ijms21155186] [Citation(s) in RCA: 163] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/15/2020] [Accepted: 07/16/2020] [Indexed: 12/14/2022] Open
Abstract
Chemokines, which are basic proteins that exert their effects via G protein-coupled receptors and a subset of the cytokine family, are mediators deeply involved in leukocyte migration during an inflammatory reaction. Chemokine (C-C motif) ligand 20 (CCL20), also known as macrophage inflammatory protein (MIP)-3α, liver activation regulated chemokine (LARC), and Exodus-1, is a small protein that is physiologically expressed in the liver, colon, and skin, is involved in tissue inflammation and homeostasis, and has a specific receptor C-C chemokine receptor 6 (CCR6). The CCL20-CCR6 axis has long been known to be involved in inflammatory and infectious diseases, such as rheumatoid arthritis and human immunodeficiency virus infections. Recently, however, reports have shown that the CCL20-CCR6 axis is associated with several cancers, including hepatocellular carcinoma, colorectal cancer, breast cancer, pancreatic cancer, cervical cancer, and kidney cancer. The CCL20-CCR6 axis promotes cancer progression directly by enhancing migration and proliferation of cancer cells and indirectly by remodeling the tumor microenvironment through immune cell control. The present article reviewed the role of the CCL20-CCR6 axis in cancer progression and its potential as a therapeutic target.
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Affiliation(s)
| | - Kouji Izumi
- Correspondence: ; Tel.: +81-76-265-2393; Fax: +81-76-234-4263
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21
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Han P, Cao P, Hu S, Kong K, Deng Y, Zhao B, Li F. Esophageal Microenvironment: From Precursor Microenvironment to Premetastatic Niche. Cancer Manag Res 2020; 12:5857-5879. [PMID: 32765088 PMCID: PMC7371556 DOI: 10.2147/cmar.s258215] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 06/29/2020] [Indexed: 12/15/2022] Open
Abstract
Esophageal cancer (EC) is the sixth most deadly cancer, and its incidence is still increasing year by year. Although the researches on the molecular mechanisms of EC have been widely carried out and incremental progress has been made, its overall survival rate is still low. There is cumulative evidence showing that the esophageal microenvironment plays a vital role in the development of EC. In precancerous lesions of the esophagus, high-risk environmental factors can promote the development of precancerous lesions by inducing the production of inflammatory factors and the recruitment of immune cells. In the tumor microenvironment, tumor-promoting cells can inhibit anti-tumor immunity and promote tumor progression through a variety of pathways, such as bone marrow-derived suppressor cells (MDSCs), tumor-associated fibroblasts (CAFs), and regulatory T cells (Tregs). The formation of extracellular hypoxia and acidic microenvironment and the change of extracellular matrix stiffness are also important factors affecting tumor progression and metastasis. Simultaneously, primary tumor-derived cytokines and bone marrow-derived immune cells can also promote the formation of pre-metastasis niche of EC lymph nodes, which are beneficial to EC lymph node metastasis. Further research on the specific mechanism of these processes in the occurrence, development, and metastasis of each EC subtype will support us to grasp the overall pre-cancerous prevention, targeted treatment, and metastatic assessment of EC.
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Affiliation(s)
- Peng Han
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Peng Cao
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Shan Hu
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Kangle Kong
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Yu Deng
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Bo Zhao
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Fan Li
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
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22
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The Fate of Th17 Cells is Shaped by Epigenetic Modifications and Remodeled by the Tumor Microenvironment. Int J Mol Sci 2020; 21:ijms21051673. [PMID: 32121394 PMCID: PMC7084267 DOI: 10.3390/ijms21051673] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 02/26/2020] [Accepted: 02/27/2020] [Indexed: 12/11/2022] Open
Abstract
Th17 cells represent a subset of CD4+ T cells characterized by the master transcription factor RORγt and the production of IL-17. Epigenetic modifications such as post-translational histone modifications and DNA methylation play a key role in Th17 cell differentiation and high plasticity. Th17 cells are highly recruited in many types of cancer and can be associated with good or bad prognosis. Here, we will review the remodeling of the epigenome induced by the tumor microenvironment, which may explain Th17 cell predominance. We will also discuss the promising treatment perspectives of molecules targeting epigenetic enzymes to remodel a Th17-enriched tumor microenvironment.
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23
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Kuen DS, Kim BS, Chung Y. IL-17-Producing Cells in Tumor Immunity: Friends or Foes? Immune Netw 2020; 20:e6. [PMID: 32158594 PMCID: PMC7049578 DOI: 10.4110/in.2020.20.e6] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 01/25/2020] [Accepted: 01/26/2020] [Indexed: 02/07/2023] Open
Abstract
IL-17 is produced by RAR-related orphan receptor gamma t (RORγt)-expressing cells including Th17 cells, subsets of γδT cells and innate lymphoid cells (ILCs). The biological significance of IL-17-producing cells is well-studied in contexts of inflammation, autoimmunity and host defense against infection. While most of available studies in tumor immunity mainly focused on the role of T-bet-expressing cells, including cytotoxic CD8+ T cells and NK cells, and their exhaustion status, the role of IL-17-producing cells remains poorly understood. While IL-17-producing T-cells were shown to be anti-tumorigenic in adoptive T-cell therapy settings, mice deficient in type 17 genes suggest a protumorigenic potential of IL-17-producing cells. This review discusses the features of IL-17-producing cells, of both lymphocytic and myeloid origins, as well as their suggested pro- and/or anti-tumorigenic functions in an organ-dependent context. Potential therapeutic approaches targeting these cells in the tumor microenvironment will also be discussed.
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Affiliation(s)
- Da-Sol Kuen
- Laboratory of Immune Regulation, Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea.,BK21 Plus Program, Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea
| | - Byung-Seok Kim
- Laboratory of Immune Regulation, Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea
| | - Yeonseok Chung
- Laboratory of Immune Regulation, Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea.,BK21 Plus Program, Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea
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24
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Samiei H, Sadighi-Moghaddam B, Mohammadi S, Gharavi A, Abdolmaleki S, Khosravi A, Kokhaei P, Bazzazi H, Memarian A. Dysregulation of helper T lymphocytes in esophageal squamous cell carcinoma (ESCC) patients is highly associated with aberrant production of miR-21. Immunol Res 2019; 67:212-222. [PMID: 31278653 DOI: 10.1007/s12026-019-09079-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Dysregulation of helper T (Th) cell subsets has been contributed to the initiation and propagation of esophageal squamous cell carcinoma (ESCC). Different microRNAs (miRNAs) have been reported to control the development and functions of tumor-associated immune cells in ESCC. Here, we aimed to assess the IL-10, TGF-β, IFN-γ, and IL-17a-producing CD3+CD8- T cells in association whit miR-21, miR-29b, miR-106a, and miR-155 expression in ESCC patients. A total of 34 ESCC patients including 12 newly diagnosed (ND) and 22 under-treatment (UT) cases and also 34 age-matched healthy donors were enrolled. Flow cytometric characterization of stimulated T cells was performed by staining of the cells with fluorescent conjugated specific anti-human CD3 and CD8 cell surface markers as well as IL-17a, IFN-γ, IL-10, and TGF-β intracytoplasmic cytokines. Circulating RNA was extracted from the plasma, and qRT-PCR was used to evaluate the expression of microRNAs. TGF-β plasma levels were also assessed by ELISA. Results showed that the frequency of Th cells was significantly reduced in patients. A significant increase in Treg as well as Th17 cells population in both patient subgroups was observed. ND patients showed elevated level of Th1 cells and IL-10. However the mean expression of IFN-γ was significantly decreased in Th cells. We also detected higher level of miR-21 in the ESCC patients which was significantly correlated with different subsets of Th cells. Our findings revealed that immune response related to the Th cells is highly impaired in ESCC patients. Association between miR-21 and Th subsets could be correlated with the impairment of anti-tumor immunity and ESCC pathogenesis, which could be potentially used as an important target for immunotherapeutic approaches.
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Affiliation(s)
- Hadiseh Samiei
- Student Research Committee, Department of Immunology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Bizhan Sadighi-Moghaddam
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Immunology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Saeed Mohammadi
- Infectious Diseases Research Center, Golestan University of Medical Sciences, Gorgan, Iran
- Stem Cell Research center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Abdolsamad Gharavi
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran
| | - Sara Abdolmaleki
- Student Research Committee, Department of Immunology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Ayyoob Khosravi
- Stem Cell Research center, Golestan University of Medical Sciences, Gorgan, Iran
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Parviz Kokhaei
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Immune and Gene Therapy Laboratory, Cancer Centre Karolinska, Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden
| | - Hadi Bazzazi
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
- Department of Medical Laboratory Sciences, Gorgan Branch, Islamic Azad University, Gorgan, Iran
| | - Ali Memarian
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran.
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25
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Najafi S, Mirshafiey A. The role of T helper 17 and regulatory T cells in tumor microenvironment. Immunopharmacol Immunotoxicol 2019; 41:16-24. [PMID: 30714422 DOI: 10.1080/08923973.2019.1566925] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
T helper 17 (Th17) cells were first described as a novel T helper cell lineage independent from Th1 and Th2 subsets. Th17 cells play vital roles in inflammation and tumor immunity. It causes the dissipation of antitumor immunity and contribution to the survival of tumor cells, worsening tumor growth and metastasis. Tumor-infiltrating Th17 cells were seen innumerous cancers in mice and humans. There has been an association between intratumoral Th17 cell infiltration and both good and bad prognoses. Besides the protumoral roles defined for IL-17 andTh17 cells, several reports have shown that Th17 cells also drive antitumoral immunity. Various mechanisms by which Th17 cells control tumor growth are as following: recruitment of several immune cells including DCs, CD4+ T cells, and CD8+ T cells within tumors, activation of CD8+ T cells, and probably plasticity toward Th1 phenotype, related to IFN-γ and TNF-α production. Regulatory T cells (Tregs) have been exhibited to infiltrate human tumors and are believed to restrict antitumor immunity. The effect of Treg cells has been more controversial. Whereas some studies have proposed that a high density of Treg cells within the tumor associated with a poor clinical prognosis, other studies have presented a positive clinical prognosis, underlining the importance of elucidating the clinical significance of Treg cells further. Treg and Th17 cells play both positive and negative roles in regulating antitumor immune responses. In spite of the presence of these cells, yet some tumors develop and grow. These T cells by themselves are not adequate to efficiently mount antitumor immune responses.
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Affiliation(s)
- Soheil Najafi
- a Department of Immunology , School of Public Health, International Campus, Tehran University of Medical Sciences , Tehran , Iran
| | - Abbas Mirshafiey
- b Department of Immunology , School of Public Health, Tehran University of Medical Sciences , Tehran , Iran
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26
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Pan P, Dombkowski AA, Wang LS, Stoner GD. A nutrigenetic approach for investigating the chemopreventive effects of black raspberries during the development of preneoplastic esophagi in rats. JOURNAL OF BERRY RESEARCH 2018; 8:263-274. [PMID: 30613310 PMCID: PMC6319902 DOI: 10.3233/jbr-180346] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
BACKGROUND Large epidemiological studies have shown that diets high in fruits reduce the risk of esophageal squamous cell carcinoma (ESCC). OBJECTIVE The current study investigated the effects of black raspberries (BRBs) on gene expression during the development of preneoplastic esophagi in rats. METHODS Using a post-initiation protocol, F344 rats were injected with N-nitrosomethylbenzylamine (NMBA) and then fed either a control diet or 5% BRBs. At weeks 9, 15, and 35, we euthanized subgroups of the rats and collected preneoplastic esophagi to isolate RNA samples for DNA microarray. RESULTS Along the development of NMBA-induced preneoplastic esophagi, NMBA injections led to differential expression of 1181 genes comparing to control rats, and dietary BRBs modulated 428 genes in esophagi from NMBA-treated rats. There are 137 common genes between 1181 and 428 gene sets, and BRBs significantly reversed the expression of 133 genes. These genes are associated with multiple gene oncology functions. BRBs induced an 8.8-fold gene enrichment on the pathway of inflammatory response and regulated 10 genes involved in this pathway. Among them, BRBs significantly reversed the expression of pro-inflammatory cytokines, such as CCL2, S100A8, and IL19. CONCLUSIONS BRBs exhibit strong anti-inflammatory effects against NMBA-induced rat esophageal tumorigenesis.
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Affiliation(s)
- Pan Pan
- Department of Medicine, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Alan A. Dombkowski
- Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA
| | - Li-Shu Wang
- Department of Medicine, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Gary D. Stoner
- Department of Medicine, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA
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27
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Liu J, Zheng X, Deng H, Xu B, Chen L, Wang Q, Zhou Q, Zhang D, Wu C, Jiang J. Expression of CCR6 in esophageal squamous cell carcinoma and its effects on epithelial-to-mesenchymal transition. Oncotarget 2017; 8:115244-115253. [PMID: 29383156 PMCID: PMC5777768 DOI: 10.18632/oncotarget.23318] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 11/16/2017] [Indexed: 12/17/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is the most common esophageal cancer associated with poor prognosis. We detected the expression of C-C motif chemokine receptor 6 (CCR6) and epithelial-to-mesenchymal transition (EMT) markers in esophageal tissues/cells, and evaluated the effects of CCR6 on ESCC cells proliferation, migration and invasion in response to C-C motif chemokine ligand 20 (CCL20) treatment. Our data showed CCR6 was highly expressed in ESCC cell lines (ECA-109 and TE-1), whereas kept in a low expression in normal cell lines HEEC (P < 0.001). CCL20 stimulus induced a significant decrease in the proliferation ability of ESCC (P < 0.05). The healing speed of CCL20 group was significantly higher than control in ECA-109 (P < 0.01), whereas significantly lower in αCCR6+CCL20 group than CCL20 group (P < 0.05).The number of cells permeabling through the polycarbonate membrane in CCL20 group was higher than control (P < 0.01). The cell number in αCCR6+CCL20 group was significantly reduced compared to CCL20 group in ECA-109 (P < 0.05). Moreover, after CCL20 stimulated in ECA-109, both mRNA and protein level of E-cadherin significantly decreased compared to control, while Vimentin was significantly higher. In αCCR6+CCL20 group, mRNA and protein level of E-cadherin significantly increased compared to CCL20 group, while Vimentin was much lower than CCL20 group. There was no significant difference in TE-1. In summary, high expression of CCR6 existed in the lymph node metastasis and TNM stage of ESCC. CCR6 play an important role in the regulation of tumor cell proliferation, invasion and migration. CCR6 may participate in regulating the occurrence of EMT in ESCC.
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Affiliation(s)
- Jian Liu
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, China.,Institute of Cell Therapy, Soochow University, Changzhou 213003, China
| | - Xiao Zheng
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, China.,Institute of Cell Therapy, Soochow University, Changzhou 213003, China
| | - Haifeng Deng
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, China.,Institute of Cell Therapy, Soochow University, Changzhou 213003, China
| | - Bin Xu
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, China.,Institute of Cell Therapy, Soochow University, Changzhou 213003, China
| | - Lujun Chen
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, China.,Institute of Cell Therapy, Soochow University, Changzhou 213003, China
| | - Qi Wang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, China.,Institute of Cell Therapy, Soochow University, Changzhou 213003, China
| | - Qi Zhou
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Dachuan Zhang
- Department of Pathology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Changping Wu
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, China.,Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Jingting Jiang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, China.,Institute of Cell Therapy, Soochow University, Changzhou 213003, China
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28
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2,8-Diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine potent CCR4 antagonists capable of inducing receptor endocytosis. Eur J Med Chem 2016; 115:14-25. [PMID: 26991939 DOI: 10.1016/j.ejmech.2016.02.058] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 02/22/2016] [Accepted: 02/24/2016] [Indexed: 11/23/2022]
Abstract
A number of potent 2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine CCR4 antagonists binding to the extracellular allosteric site were synthesised. (R)-N-(2,4-Dichlorobenzyl)-2-(2-(pyrrolidin-2-ylmethyl)-2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine (R)-(18a) has high affinity in both the [(125)I]-TARC binding assay with a pKi of 8.8, and the [(35)S]-GTPγS functional assay with a pIC50 of 8.1, and high activity in the human whole blood actin polymerisation assay (pA2 = 6.7). The most potent antagonists were also investigated for their ability to induce endocytosis of CCR4 and were found to internalise about 60% of the cell surface receptors, a property which is not commonly shared by small molecule antagonists of chemokine receptors.
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29
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Frick VO, Rubie C, Keilholz U, Ghadjar P. Chemokine/chemokine receptor pair CCL20/CCR6 in human colorectal malignancy: An overview. World J Gastroenterol 2016; 22:833-841. [PMID: 26811629 PMCID: PMC4716081 DOI: 10.3748/wjg.v22.i2.833] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Revised: 07/17/2015] [Accepted: 11/09/2015] [Indexed: 02/06/2023] Open
Abstract
Chemokines belong to a superfamily of small, cytokine-like proteins, which induce multiple physiological functions, particularly cytoskeletal rearrangement and compartment-specific migration through their interaction with G-protein-coupled receptors. Chemokines and their receptors have been widely acknowledged as essential and selective mediators in leukocyte migration in inflammatory response. It is now established that the chemokine/chemokine receptor system is also used by cancer cells to direct lymphatic and haematogenous spreading and additionally has an impact on the site of metastatic growth of different tumours. In recent years an increasing number of studies have drawn attention to CC-chemokine cysteine motif chemokine ligand 20 (CCL20) and its physiological sole receptor CCR6 to play a role in the onset, development and metastatic spread of various gastrointestinal cancer entities. Among various cancer types CCR6 was also demonstrated to be significantly overexpressed in colorectal cancer (CRC) and stimulation by its physiological ligand CCL20 has been reported to promote CRC cell proliferation and migration in vitro. Further, the CCL20/CCR6 system apparently plays a role in the organ-selective liver metastasis of CRC. Here we review the literature on expression patterns of CCL20 and CCR6 and their physiological interactions as well as the currently presumed role of CCL20 and CCR6 in the formation of CRC and the development of liver metastasis, providing a potential basis for novel treatment strategies.
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30
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Th17 Cell Plasticity and Functions in Cancer Immunity. BIOMED RESEARCH INTERNATIONAL 2015; 2015:314620. [PMID: 26583099 PMCID: PMC4637016 DOI: 10.1155/2015/314620] [Citation(s) in RCA: 176] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Accepted: 06/01/2015] [Indexed: 12/12/2022]
Abstract
Th17 cells represent a particular subset of T helper lymphocytes characterized by high production of IL-17 and other inflammatory cytokines. Th17 cells participate in antimicrobial immunity at mucosal and epithelial barriers and particularly fight against extracellular bacteria and fungi. While a role for Th17 cells in promoting inflammation and autoimmune disorders has been extensively and elegantly demonstrated, it is still controversial whether and how Th17 cells influence tumor immunity. Although Th17 cells specifically accumulate in many different types of tumors compared to healthy tissues, the outcome might however differ from a tumor type to another. Th17 cells were consequently associated with both good and bad prognoses. The high plasticity of those cells toward cells exhibiting either anti-inflammatory or in contrast pathogenic functions might contribute to Th17 versatile functions in the tumor context. On one hand, Th17 cells promote tumor growth by inducing angiogenesis (via IL-17) and by exerting themselves immunosuppressive functions. On the other hand, Th17 cells drive antitumor immune responses by recruiting immune cells into tumors, activating effector CD8(+) T cells, or even directly by converting toward Th1 phenotype and producing IFN-γ. In this review, we are discussing the impact of the tumor microenvironment on Th17 cell plasticity and function and its implications in cancer immunity.
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31
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Mei Z, Chen S, Chen C, Xiao B, Li F, Wang Y, Tao Z. Interleukin-23 Facilitates Thyroid Cancer Cell Migration and Invasion by Inhibiting SOCS4 Expression via MicroRNA-25. PLoS One 2015; 10:e0139456. [PMID: 26437444 PMCID: PMC4593557 DOI: 10.1371/journal.pone.0139456] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Accepted: 09/12/2015] [Indexed: 01/21/2023] Open
Abstract
Interleukin–23 (IL–23) is a conventional proinflammatory cytokine that plays a role in tumor progression by inducing inflammation in the tumor microenvironment. However, the role of IL–23 in thyroid cancer migration and invasion remains unclear. In the present study, we observed that the treatment with IL–23, induced migration and invasion in human thyroid cancer cells. Additional data demonstrate that SOCS4 negatively regulates IL-23-mediated migration and invasion. On investigating the mechanisms involved in IL–23 mediated migration and invasion, we observed that miR–25 promotes the migration and invasion of thyroid cancer cells by directly binding to the 3′-UTR of SOCS4 that leads to the inhibition of SOCS4. In addition, we also demonstrated that IL–23 increases miR–25 expression levels, and overexpressed miR–25 is involved in IL-23-associated SOCS4 inhibition and cell migration and invasion. Together, our data suggest that IL–23 induces migration and invasion in thyroid cancer cells by mediating the miR–25/SOCS4 signaling pathway.
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Affiliation(s)
- Zhidan Mei
- Department of Otolaryngology Head and Neck Surgery, Remin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, the People’s Republic of China
| | - Shiming Chen
- Department of Otolaryngology Head and Neck Surgery, Remin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, the People’s Republic of China
| | - Chen Chen
- Research Institute of Otolaryngology Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, the People’s Republic of China
| | - Bokui Xiao
- Research Institute of Otolaryngology Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, the People’s Republic of China
| | - Fen Li
- Research Institute of Otolaryngology Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, the People’s Republic of China
| | - Yongping Wang
- Department of Otolaryngology Head and Neck Surgery, Remin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, the People’s Republic of China
| | - Zezhang Tao
- Department of Otolaryngology Head and Neck Surgery, Remin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, the People’s Republic of China
- Research Institute of Otolaryngology Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, the People’s Republic of China
- * E-mail:
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32
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Liu J, Li F, Ping Y, Wang L, Chen X, Wang D, Cao L, Zhao S, Li B, Kalinski P, Thorne SH, Zhang B, Zhang Y. Local production of the chemokines CCL5 and CXCL10 attracts CD8+ T lymphocytes into esophageal squamous cell carcinoma. Oncotarget 2015; 6:24978-24989. [PMID: 26317795 PMCID: PMC4694808 DOI: 10.18632/oncotarget.4617] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 07/06/2015] [Indexed: 12/26/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a very common malignant tumor with poor prognosis in China. Chemokines secreted by tumors are pivotal for the accumulation of CD8(+) T lymphocytes within malignant lesions in several types of cancers, but the exact mechanism underlying CD8(+) T lymphocyte homing is still unknown in ESCC. In this study, we revealed that, compared with marginal tissues, the expression of both chemokine (C-C motif) ligand 5 (CCL5) and (C-X-C motif) ligand 10 (CXCL10) was upregulated in ESCC tissues. CCL5 expression was positively associated with the overall survival of patients. Meanwhile, RT-PCR data showed that the expression of CCL5 and CXCL10 was positively correlated with the local expressions of the CD8(+) T lymphocyte markers (CD8 and Granzyme B) in tumor tissues. Correspondingly, CD8(+) T lymphocytes were more frequently CCR5- and CXCR3-positive in tumor than in peripheral blood. Transwell analysis showed both CCL5 and CXCL10 were important for the chemotactic movement of CD8(+) T lymphocytes. Our data indicate that CCL5 and CXCL10 serve as the key chemokines to recruit CD8(+) T lymphocytes into ESCC tissue and may play a role in patient survival.
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Affiliation(s)
- Jinyan Liu
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Feng Li
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Yu Ping
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Liping Wang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Xinfeng Chen
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Dan Wang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Ling Cao
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Song Zhao
- Department of Thoracic surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Bing Li
- Department of Thoracic surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Pawel Kalinski
- Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Stephen H. Thorne
- Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Bin Zhang
- Robert H. Lurie Comprehensive Cancer Center, Department of Medicine-Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Yi Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
- Engineering Key Laboratory for Cell Therapy of Henan Province, Zhengzhou, Henan, P.R. China
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Yu Q, Lou XM, He Y. Preferential recruitment of Th17 cells to cervical cancer via CCR6-CCL20 pathway. PLoS One 2015; 10:e0120855. [PMID: 25768730 PMCID: PMC4359139 DOI: 10.1371/journal.pone.0120855] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Accepted: 01/27/2015] [Indexed: 12/12/2022] Open
Abstract
Our previous studies suggest that Th17 cells accumulate within tumor tissues and correlate with recurrence of cervical cancer patients. However, the source of the increased tumor-infiltrating Th17 cells remains poorly understood. We investigated the prevalence, phenotype and trafficking property of Th17 cells in patients with cervical cancer. Our results showed that Th17 cells highly aggregated within tumor tissues in an activated phenotype with markedly increased expression of CCR6. Correspondingly, level of CCL20 in the tumor tissues was significantly higher than that in non-tumor and normal control tissues, and strongly positively associated with Th17 cells. Further, in vitro migration assay showed CCL20 had effective chemotaxis to circulating Th17 cells. In conclusion, Th17 cells are recruited into tumor tissues preferentially through CCR6-CCL20 pathway, which can serve as a novel therapeutic target for cervical cancer.
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Affiliation(s)
- Qing Yu
- Department of Obstetrics and Gynecology, Hangzhou Obstetrics and Gynecology Hospital, Hangzhou First People’s Hospital, Hangzhou, China
- * E-mail:
| | - Xiang-ming Lou
- Department of Obstetrics and Gynecology, Hangzhou Obstetrics and Gynecology Hospital, Hangzhou First People’s Hospital, Hangzhou, China
| | - Yan He
- Department of Pathology, Yiwu Maternity and Child Care Hospital, Yiwu, Zhejiang Province, China
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Chen D, Li W, Liu S, Su Y, Han G, Xu C, Liu H, Zheng T, Zhou Y, Mao C. Interleukin-23 promotes the epithelial-mesenchymal transition of oesophageal carcinoma cells via the Wnt/β-catenin pathway. Sci Rep 2015; 5:8604. [PMID: 25721268 PMCID: PMC4342574 DOI: 10.1038/srep08604] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Accepted: 01/26/2015] [Indexed: 02/07/2023] Open
Abstract
As the eighth most common malignant tumour worldwide, oesophageal cancer (OC) is often diagnosed during the metastasis of its advanced stage. Interleukin (IL)-23 is an immunomodulatory cytokine that has recently been identified as a cancer-associated factor. However, the role of IL-23 in the evolution of OC remains unclear. In the present study, we found that IL-23 was significantly expressed in the tumours of OC patients suffering metastasis and demonstrated that IL-23 contributed to epithelial-mesenchymal transition (EMT) through the Wnt/β-catenin pathway, promoting the migration and invasion of OC cells. In conclusion, IL-23 plays a pivotal role in the development of OC via EMT.
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Affiliation(s)
- Deyu Chen
- Institute of Oncology, the Hospital Affiliated to Jiangsu University, Zhenjiang. 212001, China
| | - Wei Li
- 1] Institute of Oncology, the Hospital Affiliated to Jiangsu University, Zhenjiang. 212001, China [2] Department of Oncology, Jintan Hospital Affiliated to Jiangsu University, Changzhou. 213200, China
| | - Shenzha Liu
- Institute of Oncology, the Hospital Affiliated to Jiangsu University, Zhenjiang. 212001, China
| | - Yuting Su
- Institute of Oncology, the Hospital Affiliated to Jiangsu University, Zhenjiang. 212001, China
| | - Guohu Han
- Institute of Oncology, the Hospital Affiliated to Jiangsu University, Zhenjiang. 212001, China
| | - Chenchen Xu
- Department of Nuclear Medicine, the Hospital Affiliated to Jiangsu University, Zhenjiang. 212001, China
| | - Hongli Liu
- Department of Nuclear Medicine, the Hospital Affiliated to Jiangsu University, Zhenjiang. 212001, China
| | - Tingting Zheng
- Department of Nuclear Medicine, the Hospital Affiliated to Jiangsu University, Zhenjiang. 212001, China
| | - Yuepeng Zhou
- Institute of Oncology, the Hospital Affiliated to Jiangsu University, Zhenjiang. 212001, China
| | - Chaoming Mao
- 1] Institute of Oncology, the Hospital Affiliated to Jiangsu University, Zhenjiang. 212001, China [2] Department of Nuclear Medicine, the Hospital Affiliated to Jiangsu University, Zhenjiang. 212001, China
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The role of CCL20/CCR6 axis in recruiting Treg cells to tumor sites of NSCLC patients. Biomed Pharmacother 2014; 69:242-8. [PMID: 25661365 DOI: 10.1016/j.biopha.2014.12.008] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 12/01/2014] [Indexed: 01/01/2023] Open
Abstract
Inflammatory chemokine CCL20 and its receptor CCR6 have been reported to correlate with colorectal cancer patients' metastasis. However, the role of CCL20 in patients with NSCLC is not well defined. In this study, we detected the expression of CCL20 in tumor samples and corresponding adjacent ones (n=71) from patients with NSCLC using RT-PCR and observed that CCL20 showed higher expression in tumor samples (0.28±0.17) than in adjacent ones (0.20±0.13) (n=71, P=0.0056), which was also verified in protein level using IHC. Analysis results showed that CCL20 expression was positively associated with CD4 (n=80, P=0.0046), Foxp3 (n=80, P=0.0020) and IL-10 (n=61, P=0.0003) in tumor samples. And the flow data showed that Treg cells accumulated in TIL (MFI: 961±760) compared with PBMC (MFI: 683±460) (n=40, P=0.0046); and the percentage of CCR6 - the sole receptor of CCL20 - on Treg cells was higher in TIL (MFI: 1311±1268) than in PBMC (MFI: 976±780) (n=40, P=0.0219). It was interesting to find that the expression of CCL20 in tumor sites was almost 1.5-fold higher in samples from high-stage patients (III-IV stage, 0.34±0.17) compared with those from low-stage patients (I-II stage, 0.22±0.11) (P=0.0056). Furthermore, the higher expression of CCL20 was associated with a lower overall survival (P=0.0198). The IHC data showed that tumor cells were the main source of CCL20, and after treated cell line A549 with docetaxel, we found that the secretion of CCL20 was decreased heavily (n=3, P=0.0046). Our results demonstrated that CCL20 cooperated with CCR6 could recruit Treg cells to tumor sites, and chemotherapy medicine docetaxel could decrease the expression of CCL20.
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Miah AH, Abas H, Begg M, Marsh BJ, O’Flynn DE, Ford AJ, Percy JM, Procopiou PA, Richards SA, Rumley SA. Lead identification of benzimidazolone and azabenzimidazolone arylsulfonamides as CC-chemokine receptor 4 (CCR4) antagonists. Bioorg Med Chem 2014; 22:4298-311. [DOI: 10.1016/j.bmc.2014.05.021] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Revised: 05/07/2014] [Accepted: 05/12/2014] [Indexed: 11/25/2022]
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Koellensperger E, Gramley F, Preisner F, Leimer U, Germann G, Dexheimer V. Alterations of gene expression and protein synthesis in co-cultured adipose tissue-derived stem cells and squamous cell-carcinoma cells: consequences for clinical applications. Stem Cell Res Ther 2014; 5:65. [PMID: 24887580 PMCID: PMC4076640 DOI: 10.1186/scrt454] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Accepted: 04/22/2014] [Indexed: 02/08/2023] Open
Abstract
Introduction This is the first study evaluating the interactions of human adipose tissue derived stem cells (ADSCs) and human squamous cell carcinoma cells (SCCs), with regard to a prospective cell-based skin regenerative therapy and a thereby unintended co-localization of ADSCs and SCCs. Methods ADSCs were co-cultured with A431-SCCs and primary SCCs (pSCCs) in a transwell system, and cell-cell interactions were analyzed by assessing doubling time, migration and invasion, angiogenesis, quantitative real time PCR of 229 tumor associated genes, and multiplex protein assays of 20 chemokines and growth factors and eight matrix metalloproteinases (MMPS). Results of co-culture were compared to those of the respective mono-culture. Results ADSCs’ proliferation on the plate was significantly increased when co-cultured with A431-SCCs (P = 0.038). PSCCs and ADSCs significantly decreased their proliferation in co-culture if cultured on the plate (P <0.001 and P = 0.03). The migration of pSCC was significantly increased in co-culture (P = 0.009), as well as that of ADSCs in A431-SCC-co-culture (P = 0.012). The invasive behavior of pSCCs and A431-SCCs was significantly increased in co-culture by a mean of 33% and 35%, respectively (P = 0.038 and P <0.001). Furthermore, conditioned media from co-cultured ADSC-A431-SCCs and co-cultured ADSCs-pSCCs induced tube formation in an angiogenesis assay in vitro. In A431-SCC-co-culture 36 genes were up- and 6 were down-regulated in ADSCs, in A431-SCCs 14 genes were up- and 8 genes were down-regulated. In pSCCs-co-culture 36 genes were up-regulated in ADSCs, two were down-regulated, one gene was up-regulated in pSCC, and three genes were down-regulated. Protein expression analysis revealed that three proteins were exclusively produced in co-culture (CXCL9, IL-1b, and MMP-7). In A431-SCC-co-culture the concentration of 17 proteins was significantly increased compared to the ADSCs mono-culture (2.8- to 357-fold), and 15 proteins were expressed more highly (2.8- to 1,527-fold) compared to the A431-SCCs mono-culture. In pSCC-co-culture the concentration of 10 proteins was increased compared to ADSCs-mono-culture (2.5- to 77-fold) and that of 15 proteins was increased compared to pSCC mono-culture (2.6- to 480-fold). Conclusions This is the first study evaluating the possible interactions of primary human ADSCs with human SCCs, pointing towards a doubtlessly increased oncological risk, which should not be neglected when considering a clinical use of isolated human ADSCs in skin regenerative therapies.
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