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Alsousli M, Maire CL, Piffko A, Matschke J, Glau L, Reetz M, Schneegans S, Emurlai G, Asey B, Rünger A, Peine S, Kropidlowski J, Gempt J, Glatzel M, Westphal M, Tolosa E, Lamszus K, Pantel K, Joosse SA, Mohme M, Wikman H. Altered CD4 T cell response in oligometatastic non-small cell lung cancer brain metastasis. Acta Neuropathol Commun 2025; 13:95. [PMID: 40346687 PMCID: PMC12063345 DOI: 10.1186/s40478-025-02011-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Accepted: 04/21/2025] [Indexed: 05/11/2025] Open
Abstract
Lung cancer is the leading cause of cancer mortality globally, with brain metastasis (BM) in 40% of advanced non-small-cell lung cancer (NSCLC) cases. In 15% of these cases, the brain is the sole affected organ (oligometastasis), which correlates with a better prognosis compared to widespread disease. It remains unclear if brain-only metastasis without systemic spread is due to the immune system's ability to control systemic tumor progression. We studied the immune cell compositions in NSCLC patients with BM, identifying novel patterns associated with BM, and specifcally with either oligo- or polymetastatic spread. Multi-parametric immune phenotyping of peripheral blood primarily showed alterations in the CD4+ T cell compartment, with increased CD4+ TH17 cells, and higher IL-17 levels in NSCLC BM patients compared to healthy individuals. Furthermore, CD4+ T cells in BM patients exhibited lower CD73 expression and reduced effector memory differentiation. There was also decreased intratumoral infiltration and a distinct CD4+ T cell profile in oligo-synchronous BM, both in the tumor microenvironment and peripheral blood, compared to polymetastatic BM patients. Additionally, CD73 was significantly upregulated in CD4+ and T regulatory cells of oligo-synchronous (BM simulantously with primary-tumor diagnosis) BM. These findings suggest that CD4+ T cells play a crucial role in the biology of NSCLC BM and potentially contribute to differences in metastatic patterns, as oligo-synchronous BM shows a more significant alteration in the CD4+ T cell immune profile, both locally at the tumor site and systemically.
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Affiliation(s)
- Mais Alsousli
- Department of Tumor Biology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany
| | - Cecile L Maire
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andras Piffko
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jakob Matschke
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Laura Glau
- Institute of Immunology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Merle Reetz
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Svenja Schneegans
- Department of Tumor Biology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany
| | - Gresa Emurlai
- Department of Tumor Biology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany
| | - Benedikt Asey
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alessandra Rünger
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sven Peine
- Institute of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jolanthe Kropidlowski
- Department of Tumor Biology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany
| | - Jens Gempt
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Markus Glatzel
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Manfred Westphal
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eva Tolosa
- Institute of Immunology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Katrin Lamszus
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Klaus Pantel
- Department of Tumor Biology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany
| | - Simon A Joosse
- Department of Tumor Biology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany
- Mildred Scheel Cancer Career Center HaTriCS4, Hamburg, Germany
| | - Malte Mohme
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Harriet Wikman
- Department of Tumor Biology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany.
- Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
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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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Zhang R, Chen S, Luo T, Guo S, Qu J. Activated Tim-3/Galectin-9 participated in the development of multiple myeloma by negatively regulating CD4 T cells. Hematology 2024; 29:2288481. [PMID: 38108336 DOI: 10.1080/16078454.2023.2288481] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 11/15/2023] [Indexed: 12/19/2023] Open
Abstract
The interaction between Tim-3 on T cells and its ligand Galectin-9 negatively regulates the cellular immune response. However, the regulation of Tim-3/Galectin-9 on CD4 T cell subsets in multiple myeloma (MM) remains unclear. The aim of this study was to investigate the relationship between the regulation of CD4 T cell subsets by the Tim-3/Galectin-9 pathway and clinical prognostic indicators in MM. Tim-3/Galectin-9 were detected by flow cytometry, PCR and ELISA in 60 MM patients and 40 healthy controls, and its correlation with clinical prognostic parameters was analyzed. The expressions of Tim-3 on CD4 T cells, Galectin-9 mRNA in PBMC and level of Galectin-9 protein in serum were significantly elevated in MM patients, especially those with poor prognostic indicators. In MM patients, Tim-3 was highly expressed on the surfaces of Th1, Th2, and Th17 cells, but lowly expressed on Treg. Moreover, level of cytokine IFN-γ in serum was negatively correlated with Tim-3+Th1 cell and Galectin-9mRNA, Galectin-9 protein level. In addition, cell culture experiments showed that the anti-tumor effect and the ability to secrete IFN-γ were restored by blocking the Tim-3/Galectin-9 pathway. In MM patients, Tim-3/Galectin-9 is elevated and associated with disease progression, by inhibiting the cytotoxic function of Th1, and also promoting Th2 and Th17 to be involved in immune escape of MM. Therefore, Tim-3/Galectin-9 may serve as a new immunotherapeutic target for MM patients.
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Affiliation(s)
- Rui Zhang
- Center of Hematology, the First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous, Xinjing, People's Republic of China
- Hematology Institute of Xinjiang Uygur Autonomous Region, Xinjing, People's Republic of China
| | - Shuang Chen
- Center of Hematology, the First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous, Xinjing, People's Republic of China
- Hematology Institute of Xinjiang Uygur Autonomous Region, Xinjing, People's Republic of China
| | - Tingting Luo
- Center of Hematology, the First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous, Xinjing, People's Republic of China
- Hematology Institute of Xinjiang Uygur Autonomous Region, Xinjing, People's Republic of China
| | - Sha Guo
- Center of Hematology, the First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous, Xinjing, People's Republic of China
- Hematology Institute of Xinjiang Uygur Autonomous Region, Xinjing, People's Republic of China
| | - Jianhua Qu
- Center of Hematology, the First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous, Xinjing, People's Republic of China
- Hematology Institute of Xinjiang Uygur Autonomous Region, Xinjing, People's Republic of China
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Anvar MT, Rashidan K, Arsam N, Rasouli-Saravani A, Yadegari H, Ahmadi A, Asgari Z, Vanan AG, Ghorbaninezhad F, Tahmasebi S. Th17 cell function in cancers: immunosuppressive agents or anti-tumor allies? Cancer Cell Int 2024; 24:355. [PMID: 39465401 PMCID: PMC11514949 DOI: 10.1186/s12935-024-03525-9] [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: 08/13/2024] [Accepted: 10/08/2024] [Indexed: 10/29/2024] Open
Abstract
T helper (Th) 17 cells, a distinct subset of Th lymphocytes, are known for their prominent interleukin (IL)-17 production and other pro-inflammatory cytokines. These cells exhibit remarkable plasticity, allowing them to exhibit different phenotypes in the cancer microenvironment. This adaptability enables Th17 cells to promote tumor progression by immunosuppressive activities and angiogenesis, but also mediate anti-tumor immune responses through employing immune cells in tumor setting or even by directly converting toward Th1 phenotype and producing interferon-gamma (IFN-γ). This dual role of Th17 cells in cancer makes it a double-edged sword in encountering cancer. In this review, we aim to elucidate the complexities of Th17 cell function in cancer by summarizing recent studies and, ultimately, to design novel therapeutic strategies, especially targeting Th17 cells in the tumor milieu, which could pave the way for more effective cancer treatments.
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Affiliation(s)
- Milad Taghizadeh Anvar
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kimiya Rashidan
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nima Arsam
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ashkan Rasouli-Saravani
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamidreza Yadegari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Ahmadi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zeynab Asgari
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ahmad Ghorbani Vanan
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Farid Ghorbaninezhad
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Safa Tahmasebi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Dimitriou F, Cheng PF, Saltari A, Schaper-Gerhardt K, Staeger R, Haunerdinger V, Sella F, Tastanova A, Urban C, Dettwiler S, Mihic-Probst D, Matter CM, Michielin O, Gutzmer R, Long GV, Becher B, Levesque MP, Dummer R. A targetable type III immune response with increase of IL-17A expressing CD4 + T cells is associated with immunotherapy-induced toxicity in melanoma. NATURE CANCER 2024; 5:1390-1408. [PMID: 39210005 PMCID: PMC11424476 DOI: 10.1038/s43018-024-00810-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 07/18/2024] [Indexed: 09/04/2024]
Abstract
Immune checkpoint inhibitors are standard-of-care for the treatment of advanced melanoma, but their use is limited by immune-related adverse events. Proteomic analyses and multiplex cytokine and chemokine assays from serum at baseline and at the adverse event onset indicated aberrant T cell activity with differential expression of type I and III immune signatures. This was in line with the finding of an increase in the proportion of CD4+ T cells with IL-17A expression at the adverse event onset in the peripheral blood using flow cytometry. Multiplex immunohistochemistry and spatial transcriptomics on immunotherapy-induced skin rash and colitis showed an increase in the proportion of CD4+ T cells with IL-17A expression. Anti-IL-17A was administered in two patients with mild myocarditis, colitis and skin rash with resolution of the adverse events. This study highlights the potential role of type III CD4+ T cells in adverse event development and provides proof-of-principle evidence for a clinical trial using anti-IL-17A for treating adverse events.
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Affiliation(s)
- Florentia Dimitriou
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.
- Faculty of Medicine, University of Zurich, Zurich, Switzerland.
| | - Phil F Cheng
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
- Department of Oncology, Geneva University Hospital, Geneva, Switzerland
| | - Annalisa Saltari
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Katrin Schaper-Gerhardt
- Department of Dermatology, Johannes Wesling Medical Center, Ruhr University Bochum Campus Minden, Minden, Germany
- Department of Dermatology, Medical School Hannover, Hannover, Germany
| | - Ramon Staeger
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Veronika Haunerdinger
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Federica Sella
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Aizhan Tastanova
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Christian Urban
- Functional Genomics Center Zurich, University of Zurich/ETH Zurich, Zurich, Switzerland
| | - Susanne Dettwiler
- Institute for Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Daniela Mihic-Probst
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
- Institute for Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Christian M Matter
- Department of Cardiology, University Heart Center and Center for Experimental Cardiology (CTEC), University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Olivier Michielin
- Department of Oncology, Geneva University Hospital, Geneva, Switzerland
| | - Ralf Gutzmer
- Department of Dermatology, Johannes Wesling Medical Center, Ruhr University Bochum Campus Minden, Minden, Germany
| | - Georgina V Long
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia
- Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Burkhard Becher
- Institute of Experimental Immunology, University of Zurich (UZH), Zurich, Switzerland
| | - Mitchell P Levesque
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Reinhard Dummer
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.
- Faculty of Medicine, University of Zurich, Zurich, Switzerland.
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Schmälter AK, Löhr P, Konrad M, Waidhauser J, Arndt TT, Schiele S, Thoma A, Hackanson B, Rank A. Alterations in Peripheral Lymphocyte Subsets under Immunochemotherapy in Stage IV SCLC Patients: Th17 Cells as Potential Early Predictive Biomarker for Response. Int J Mol Sci 2024; 25:5056. [PMID: 38791096 PMCID: PMC11121216 DOI: 10.3390/ijms25105056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 04/29/2024] [Accepted: 04/30/2024] [Indexed: 05/26/2024] Open
Abstract
UICC stage IV small-cell lung cancer (SCLC) is a highly aggressive malignancy without curative treatment options. Several randomized trials have demonstrated improved survival rates through the addition of checkpoint inhibitors to first-line platin-based chemotherapy. Consequently, a combination of chemo- and immunotherapy has become standard palliative treatment. However, no reliable predictive biomarkers for treatment response exist. Neither PD-L1 expression nor tumor mutational burden have proven to be effective predictive biomarkers. In this study, we compared the cellular immune statuses of SCLC patients to a healthy control cohort and investigated changes in peripheral blood B, T, and NK lymphocytes, as well as several of their respective subsets, during treatment with immunochemotherapy (ICT) using flow cytometry. Our findings revealed a significant decrease in B cells, while T cells showed a trend to increase throughout ICT. Notably, high levels of exhausted CD4+ and CD8+ cells, alongside NK subsets, increased significantly during treatment. Furthermore, we correlated decreases/increases in subsets after two cycles of ICT with survival. Specifically, a decrease in Th17 cells indicated a better overall survival. Based on these findings, we suggest conducting further investigation into Th17 cells as a potential early predictive biomarkers for response in patients receiving palliative ICT for stage IV SCLC.
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Affiliation(s)
- Ann-Kristin Schmälter
- Department of Hematology and Oncology, Augsburg University Hospital and Medical Faculty, Comprehensive Cancer Center Augsburg, 86156 Augsburg, Germany; (P.L.); (M.K.); (J.W.); (A.T.); (B.H.); (A.R.)
- Bavarian Cancer Research Center (BZKF), 86156 Augsburg, Germany
| | - Phillip Löhr
- Department of Hematology and Oncology, Augsburg University Hospital and Medical Faculty, Comprehensive Cancer Center Augsburg, 86156 Augsburg, Germany; (P.L.); (M.K.); (J.W.); (A.T.); (B.H.); (A.R.)
- Bavarian Cancer Research Center (BZKF), 86156 Augsburg, Germany
| | - Maik Konrad
- Department of Hematology and Oncology, Augsburg University Hospital and Medical Faculty, Comprehensive Cancer Center Augsburg, 86156 Augsburg, Germany; (P.L.); (M.K.); (J.W.); (A.T.); (B.H.); (A.R.)
| | - Johanna Waidhauser
- Department of Hematology and Oncology, Augsburg University Hospital and Medical Faculty, Comprehensive Cancer Center Augsburg, 86156 Augsburg, Germany; (P.L.); (M.K.); (J.W.); (A.T.); (B.H.); (A.R.)
| | - Tim Tobias Arndt
- Institute of Mathematics, University of Augsburg, 86159 Augsburg, Germany; (T.T.A.); (S.S.)
| | - Stefan Schiele
- Institute of Mathematics, University of Augsburg, 86159 Augsburg, Germany; (T.T.A.); (S.S.)
| | - Alicia Thoma
- Department of Hematology and Oncology, Augsburg University Hospital and Medical Faculty, Comprehensive Cancer Center Augsburg, 86156 Augsburg, Germany; (P.L.); (M.K.); (J.W.); (A.T.); (B.H.); (A.R.)
| | - Björn Hackanson
- Department of Hematology and Oncology, Augsburg University Hospital and Medical Faculty, Comprehensive Cancer Center Augsburg, 86156 Augsburg, Germany; (P.L.); (M.K.); (J.W.); (A.T.); (B.H.); (A.R.)
- Bavarian Cancer Research Center (BZKF), 86156 Augsburg, Germany
- Department of Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Andreas Rank
- Department of Hematology and Oncology, Augsburg University Hospital and Medical Faculty, Comprehensive Cancer Center Augsburg, 86156 Augsburg, Germany; (P.L.); (M.K.); (J.W.); (A.T.); (B.H.); (A.R.)
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Wang H, Tang H, Yuan S, Liang C, Li Y, Zhu S, Chen K. IL-17A deficiency inhibits lung cancer-induced osteoclastogenesis by promoting apoptosis of osteoclast precursor cells. PLoS One 2024; 19:e0299028. [PMID: 38394046 PMCID: PMC10889641 DOI: 10.1371/journal.pone.0299028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 02/02/2024] [Indexed: 02/25/2024] Open
Abstract
Osteoclasts are crucial in the events leading to bone metastasis of lung cancer. Interleukin-17A (IL-17A) affects osteogenesis by regulating the survival of osteoclast precursors (OCPs) and is enriched in lung cancer cells. However, how factors derived from tumor cells that metastasize to bone affect osteoclastogenesis remains poorly understood. We examined whether IL-17A derived from lung cancer cells affects osteoclast differentiation by regulating OCP apoptosis. IL-17A expression was inhibited in A549 non-small cell lung cancer cells using RNA interference. Compared with conditioned medium (CM) from A549 cells (A549-CM), CM from IL-17A-deficient A549 cells (A549-si-CM) suppressed osteoclastogenesis. The mRNA expression of osteoclast-specific genes was downregulated following A549-si-CM treatment. Furthermore, A549-si-CM promoted osteoclast precursor apoptosis at an early stage of osteoclastogenesis, which was related to the promotion of caspase-3 expression by A549-si-CM during osteoclast differentiation. In vivo experiments also showed that inhibition of IL-17A expression in A549 cells reduced osteoclast activation and bone tissue destruction. Collectively, our results indicate that IL-17A deficiency inhibits lung cancer-induced osteoclast differentiation by promoting apoptosis of osteoclast precursors in the early stage of osteoclast formation and that IL-17A is a potential therapeutic target for cancer-associated bone resorption in patients with lung cancer.
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Affiliation(s)
- Hongkai Wang
- Department of Orthopedics, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
- Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Hao Tang
- Department of Orthopedics, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
- Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Shujie Yuan
- Department of Orthopedics, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Chuntao Liang
- Department of Orthopedics, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Yuanxin Li
- Department of Orthopedics, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Shida Zhu
- Department of Orthopedics, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Kai Chen
- Department of Orthopedics, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
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Wang W, Song J, Lu N, Yan J, Chen G. Sanghuangporus sanghuang extract inhibits the proliferation and invasion of lung cancer cells in vitro and in vivo. Nutr Res Pract 2023; 17:1070-1083. [PMID: 38053828 PMCID: PMC10694423 DOI: 10.4162/nrp.2023.17.6.1070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 09/01/2023] [Accepted: 10/23/2023] [Indexed: 12/07/2023] Open
Abstract
BACKGROUND/OBJECTIVES Sanghuangporus sanghuang (SS) has various medicinal effects, including anti-inflammation and anticancer activities. Despite the extensive research on SS, its molecular mechanisms of action on lung cancer are unclear. This study examined the impact of an SS alcohol extract (SAE) on lung cancer using in vitro and in vivo models. MATERIALS/METHODS Different concentrations of SAE were used to culture lung cancer cells (A549 and H1650). A cell counting kit-8 assay was used to detect the survival ability of A549 and H1650 cells. A scratch assay and transwell cell invasion assay were used to detect the migration rate and invasive ability of SAE. Western blot analysis was used to detect the expression of B-cell lymphoma-2 (Bcl-2), Bcl2-associated X (Bax), cyclin D1, cyclin-dependent kinases 4 (CDK4), signal transducer and activator of transcription 3 (STAT3), and phosphorylated STAT3 (p-STAT3). Lung cancer xenograft mice were used to detect the inhibiting ability of SAE in vivo. Hematoxylin and eosin staining and immunohistochemistry were used to detect the effect of SAE on the structural changes to the tumor and the expression of Bcl-2, Bax, cyclin D1, CDK4, STAT3, and p-STAT3 in lung cancer xenograft mice. RESULTS SAE could inhibit lung cancer proliferation significantly in vitro and in vivo without cytotoxicity. SAE suppressed the viability, migration, and invasion of lung cancer cells in a dose and time-dependent manner. The SAE treatment significantly decreased the proapoptotic Bcl-2/Bax ratio and the expression of pro-proliferative proteins Cyclin D1 and CDK4 in vitro and in vivo. Furthermore, SAE also inhibited STAT3 expression. CONCLUSIONS SAE reduced the cell viability and suppressed cell migration and invasion in human lung cancer cells. Moreover, SAE also exhibited anti-proliferation effects in vivo. Therefore, SAE may have benefits in cancer therapy.
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Affiliation(s)
- Weike Wang
- Institute of Vegetable Science, Hangzhou Academy of Agricultural Sciences, Hangzhou 310024, China
| | - Jiling Song
- Institute of Vegetable Science, Hangzhou Academy of Agricultural Sciences, Hangzhou 310024, China
| | - Na Lu
- Institute of Vegetable Science, Hangzhou Academy of Agricultural Sciences, Hangzhou 310024, China
| | - Jing Yan
- Institute of Vegetable Science, Hangzhou Academy of Agricultural Sciences, Hangzhou 310024, China
| | - Guanping Chen
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China
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9
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Peng Z, Dong X, He M, Zhao Y, Liu Y, Li M, Li G, Wang X, Li L, Hu Y. Elevated profiles of peripheral Th22, Th17, Th2 cells, and decreased percentage of Th1 cells in breast cancer patients. Thorac Cancer 2023; 14:3282-3294. [PMID: 37732365 PMCID: PMC10665788 DOI: 10.1111/1759-7714.15119] [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: 07/23/2023] [Revised: 09/10/2023] [Accepted: 09/11/2023] [Indexed: 09/22/2023] Open
Abstract
BACKGROUND Th22 subset is a particular type of CD4+ T helper cells subset. Our study aimed to explore the expression level of circulating Th22, Th17, Th1, and Th2 cells and the possible mechanism of these cells in breast cancer (BC) with different pathological features. METHODS Our study enrolled 43 newly diagnosed BC patients and 30 healthy controls. Frequencies of peripheral Th22, Th17, Th1, and Th2 cells were tested by flow cytometry. Concentrations of IL-22 cytokine in plasma were examined by enzyme-linked immunosorbent assay (ELISA). Real-time PCR was done to test aromatic hydrocarbon receptor (AHR) and RAR-associated orphan receptor C (RORC) gene expression. RESULTS Frequencies of Th22, Th17, Th2 subsets, and the plasma IL-22 level was obviously higher in the BC patients. A positive correlation between Th22 frequency and IL-22 concentration in plasma was detected in BC patients. Furthermore, the percentage of Th22, Th2 subsets in peripheral blood of HER2 positive BC was higher than that in HER2 negative BC patients. A negative correlation between Th1 subset and Ki-67% as well as a positive correlation between Th2 subset and Ki-67% was found in BC patients. The proportion of Th1 cells in BC patients was significantly lower than that of the control group. Expression of AHR and RORC transcription factors were also observed to be upregulated in the BC patients. Furthermore, Th22 cells were positively correlated with BC tumor stage and clinical outcomes. The BC patients with a higher percentage of Th22, Th17, Th1 cells or a lower percentage of Th1 cells showed a decreased trend of survival rate. CONCLUSION Th22, Th17, Th1, and Th2 subsets may play an essential role in BC patients. Th22, Th17, Th1, and Th2 cells may have potential significance to be used as clinical markers in BC patients with different molecular classification. Th22 cells may have potential value in BC patients' outcomes prediction, providing clinical value.
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Affiliation(s)
- Zhiguo Peng
- Department of Organ Transplantation, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Xinyue Dong
- Department of OncologyQilu Hospital of Shandong University Dezhou HospitalDezhouChina
| | - Miao He
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Yajing Zhao
- Department of Hematology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Yujia Liu
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Mo Li
- Department of OncologyWeifang People's HospitalWeifangChina
| | - Guosheng Li
- Department of Hematology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Xiuwen Wang
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Li Li
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Yu Hu
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
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10
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Liu L, Liu R, Wei C, Li D, Gao X. The role of IL-17 in lung cancer growth. Cytokine 2023; 169:156265. [PMID: 37348188 DOI: 10.1016/j.cyto.2023.156265] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 05/27/2023] [Accepted: 06/01/2023] [Indexed: 06/24/2023]
Abstract
Interleukin 17 (IL-17) is an inflammatory cytokine with multiple roles in immune protection, immunopathology, and inflammation-related tumors. Lung cancer is inflammation-related cancer, and a large number of studies have shown that IL-17 contributes to the metastasis and progression of lung cancer. However, some studies have shown that IL17 inhibits the occurrence of lung cancer. At present, there is still some controversy about the role of IL17 in the occurrence and development of lung cancer. This review introduces the basic characteristics of IL-17 and focuses on its role in lung cancer, in order to provide a certain theoretical basis for the prevention, diagnosis, and treatment of lung cancer.
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Affiliation(s)
- Liping Liu
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Renli Liu
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Chaojie Wei
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Dong Li
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China.
| | - Xiuzhu Gao
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, China.
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11
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Wang H, Huang H, Lin X, Chi P, Chen H, Chen J, Mou Y, Chen Z, Yang Q, Guo C. Dynamic analysis of immune status in patients with intracranial germ cell tumor and establishment of an immune risk prognostic model. Front Immunol 2022; 13:1010146. [PMID: 36304453 PMCID: PMC9592720 DOI: 10.3389/fimmu.2022.1010146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 09/20/2022] [Indexed: 11/25/2022] Open
Abstract
Introduction Immune status was evaluated by means of lymphocyte subset counts and immune factors in cancer. This study analyzed the peripheral blood immune index and survival outcomes in intracranial germ cell tumor (iGCT) patients. Methods Peripheral blood lymphocyte subset counts and levels of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF), and interferon-γ (IFN) from 133 iGCT patients were collected and retrospectively analyzed. Their clinical information was extracted from the hospital database, and prognosis was confirmed by telephone visit. Patients (n=11) underwent prospective review and their samples of peripheral blood lymphocytes were verified. Results A total of 113 (84.2%) patients received comprehensive treatments, including 96 standard therapy (combination of full course chemotherapy and radiology with or without surgery) and 17 comprehensive but non-standard therapy (either without full course chemotherapy or with non-standard radiotherapy) and 98 (73.7%) reached complete or partial response. T lymphocytes (CD3+), cytotoxic T cells (CD3+CD8+ or Tc), and B lymphocytes (CD19+) decreased (p=0.047, p=0.004, and p<0.001, respectively), while activated cytotoxic T lymphocytes (CD8+CD25+) and IFN increased (p<0.001 and p=0.002, respectively) after treatment. Median survival was 45.33 months, and patients with increased Tc cells and activated Tc cells as well as IFN presented encouraging outcomes (p=0.039, p=0.041, and p=0.017 respectively). Regression analysis showed that non-increased Tc cells and non-increased activated Tc cells were independent factors of poor prognosis (p=0.016, HR=3.96, 95%CI=1.288-12.20; p=0.002, HR=4.37 95%CI= 1.738-10.97). Standard chemo-radiotherapy was independently related to reduced risk of death(p=0.022, HR=0.19, 95%CI=0.044-0.79). Consistence was seen in a nomogram established through retro and prospective studies. An immune risk model indicated the activated group (with both increased activated T cells and IFN levels) had the best prognosis, the mildly activated type with elevated IFN levels had intermediate outcome, and patients with the silent immune status had the worst outcomes (Log rank test, p=0.011). Conclusion Implementation of standard comprehensive treatments led to positive responses. Dynamic monitoring of peripheral blood lymphocyte subsets can be used as an auxiliary indicator for prognosis judgment.
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Affiliation(s)
- Hairong Wang
- Department of Neurosurgery/Neuro-oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - He Huang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiaoping Lin
- Department of Nuclear Medicine, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Peidong Chi
- Department of Clinical Laboratory, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Hongyu Chen
- Department of Neurosurgery/Neuro-oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jiangen Chen
- Department of Neurosurgery/Neuro-oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yonggao Mou
- Department of Neurosurgery/Neuro-oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhongping Chen
- Department of Neurosurgery/Neuro-oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qunying Yang
- Department of Neurosurgery/Neuro-oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Chengcheng Guo
- Department of Neurosurgery/Neuro-oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- *Correspondence: Chengcheng Guo, ; Qunying Yang, ; Zhongping Chen,
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12
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Liu Y, Zhang X, Cheng X, Luo Q, Yu M, Long K, Qu W, Tang Y, Gong M, Liang L, Ke X, Song Y. Characterization of fatty acid metabolism-related lncRNAs in lung adenocarcinoma identifying potential novel prognostic targets. Front Genet 2022; 13:990153. [PMID: 36299578 PMCID: PMC9589892 DOI: 10.3389/fgene.2022.990153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 09/01/2022] [Indexed: 11/15/2022] Open
Abstract
Lung adenocarcinoma (LUAD), a malignant respiratory tumor with an extremely poor prognosis, has troubled the medical community all over the world. According to recent studies, fatty acid metabolism (FAM) and long non-coding RNAs (lncRNAs) regulation have shown exciting results in tumor therapy. In this study, the original LUAD patient data was obtained from the TCGA database, and 12 FAM-related lncRNAs (AL390755.1, AC105020.6, TMPO-AS1, AC016737.2, AC127070.2, LINC01281, AL589986.2, GAS6-DT, AC078993.1, LINC02198, AC007032.1, and AL021026.1) that were highly related to the progression of LUAD were finally identified through bioinformatics analysis, and a risk score model for clinical reference was constructed. The window explores the immunology and molecular mechanism of LUAD, aiming to shed the hoping light on LUAD treatment.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Xixian Ke
- *Correspondence: Xixian Ke, ; Yongxiang Song,
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13
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Xu L, Zou C, Zhang S, Chu TSM, Zhang Y, Chen W, Zhao C, Yang L, Xu Z, Dong S, Yu H, Li B, Guan X, Hou Y, Kong FM. Reshaping the systemic tumor immune environment (STIE) and tumor immune microenvironment (TIME) to enhance immunotherapy efficacy in solid tumors. J Hematol Oncol 2022; 15:87. [PMID: 35799264 PMCID: PMC9264569 DOI: 10.1186/s13045-022-01307-2] [Citation(s) in RCA: 97] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 06/22/2022] [Indexed: 02/07/2023] Open
Abstract
The development of combination immunotherapy based on the mediation of regulatory mechanisms of the tumor immune microenvironment (TIME) is promising. However, a deep understanding of tumor immunology must involve the systemic tumor immune environment (STIE) which was merely illustrated previously. Here, we aim to review recent advances in single-cell transcriptomics and spatial transcriptomics for the studies of STIE, TIME, and their interactions, which may reveal heterogeneity in immunotherapy responses as well as the dynamic changes essential for the treatment effect. We review the evidence from preclinical and clinical studies related to TIME, STIE, and their significance on overall survival, through different immunomodulatory pathways, such as metabolic and neuro-immunological pathways. We also evaluate the significance of the STIE, TIME, and their interactions as well as changes after local radiotherapy and systemic immunotherapy or combined immunotherapy. We focus our review on the evidence of lung cancer, hepatocellular carcinoma, and nasopharyngeal carcinoma, aiming to reshape STIE and TIME to enhance immunotherapy efficacy.
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Affiliation(s)
- Liangliang Xu
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, 518053, China
| | - Chang Zou
- Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, 518020, China.,Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Shenzhen, Guangdong, 518020, China.,Key Laboratory of Medical Electrophysiology of Education Ministry, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, China
| | - Shanshan Zhang
- Department of Chemical Biology, School of Life and Marine Sciences, Shenzhen University, Shenzhen, Guangdong, 518000, China
| | - Timothy Shun Man Chu
- Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK.,Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK
| | - Yan Zhang
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, 518053, China
| | - Weiwei Chen
- Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Caining Zhao
- Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Li Yang
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, 518053, China
| | - Zhiyuan Xu
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, 518053, China
| | - Shaowei Dong
- Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, 518020, China
| | - Hao Yu
- Chinese Academy of Sciences Shenzhen Institutes of Advanced Technology, Shenzhen, Guangdong, 518055, China
| | - Bo Li
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, 518107, China
| | - Xinyuan Guan
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, 518053, China. .,Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China. .,Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, Guangdong, 528200, China.
| | - Yuzhu Hou
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
| | - Feng-Ming Kong
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, 518053, China. .,Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
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14
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Xu R, Ke X, Shang W, Liu S, Fu X, Wang T, Jin S. Distribution and Clinical Significance of IL-17A in Tumor-Infiltrating Lymphocytes of Non-Small Cell Lung Cancer Patients. Pathol Oncol Res 2022; 28:1610384. [PMID: 35665407 PMCID: PMC9156623 DOI: 10.3389/pore.2022.1610384] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 04/27/2022] [Indexed: 11/13/2022]
Abstract
Objective: To investigate the distribution of IL-17A and its clinical significance in tumor infiltrating lymphocytes (TILs) of patients with non-small cell lung cancer (NSCLC). Methods: Expression level of IL-17A in TILs of 3 paired NSCLC and paracancerous specimens was measured by qRT-PCR. The distribution of IL-17A in immune cell subsets of 15 paired NSCLC and paracancerous specimens was examined by flow cytometry. The correlation between IL-17A and clinical features of NSCLC was identified. Results: IL-17A was significantly upregulated in TILs of NSCLC specimens than those of paracancerous ones (p < 0.0001). Meanwhile, T helper 17 cells (Th17 cells, p < 0.001), IL-17-secreting CD8+ T cells (Tc17 cells, p < 0.001) and IL-17-producing cells (γδT17 cells, p < 0.0001) were significantly abundant in TILs of NSCLC specimens than those of controls, and the higher abundance of the latter was much pronounced than that of the former two. Moreover, γδT17 cells in TILs were significantly correlated with lymphatic metastasis and CYFRA 21-1 level of NSCLC patients (p < 0.05). Conclusion: Tumor infiltrated γδT cells are the main source of IL-17 in early-stage NSCLC, and IL-17 may be a vital regulator involved in the development of NSCLC.
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Affiliation(s)
- Rui Xu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China
| | - Xing Ke
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenwen Shang
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China
| | - Shuna Liu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China
| | - Xin Fu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China
| | - Ting Wang
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China
| | - Shuxian Jin
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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15
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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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Anderson R, Blidner AG, Rapoport BL. Frontiers in Pharmacology: Review Manuscript Targeting of the Neutrophil as an Adjunctive Strategy in Non-Small Cell Lung Cancer. Front Pharmacol 2021; 12:676399. [PMID: 34168563 PMCID: PMC8218630 DOI: 10.3389/fphar.2021.676399] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 05/17/2021] [Indexed: 01/14/2023] Open
Abstract
Lung cancer remains the leading cause of cancer mortality in the United States, with non-small cell lung cancer (NSCLC) accounting for around 85% of cases. Of particular concern is the poor responsiveness of this malignancy to therapy, resulting in a very low 5-year survival rate (17.4%) and a prominent tendency to progress to metastatic disease. A number of very recent studies, both pre-clinical and clinical, have implicated the neutrophil in both the pathogenesis and unsatisfactory response to therapy of NSCLC. In this context, movement of neutrophils into the tumor microenvironment (TME) is a common feature of NSCLC. Indeed neutrophils are the dominant type of immune cell in the NSCLC TME, creating a highly immunosuppressive milieu that is not only conducive to tumor growth and spread, but also represents a significant obstacle to the success of anti-tumor therapy, especially novel immunotherapies. The clinically relevant adverse impact of a neutrophil predominance both systemically and in the TME of patients with NSCLC is underscored by the negative prognostic value of both a persistent neutrophilia and, in particular, a high (≥5) neutrophil:lymphocyte ratio. On a more positive note, however, recognition of the involvement of the neutrophil in both the pathophysiology of NSCLC and treatment failure has enabled identification of neutrophil-targeted strategies that have the potential to serve as adjuncts to standard anti-cancer therapies, including immunotherapy. These strategies together with a consideration of the immunosuppressive, pro-tumorigenic properties of the neutrophil represent the major thrusts of this review.
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Affiliation(s)
- Ronald Anderson
- Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - Ada Gabriela Blidner
- Laboratory of Immunopathology, Institute of Biology and Experimental Medicine CONICET, Buenos Aires, Argentina
| | - Bernardo Leon Rapoport
- Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.,The Medical Oncology Centre of Rosebank, Johannesburg, South Africa
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Zhang Z, Zeng P, Gao W, Zhou Q, Feng T, Tian X. Circadian clock: a regulator of the immunity in cancer. Cell Commun Signal 2021; 19:37. [PMID: 33752691 PMCID: PMC7986390 DOI: 10.1186/s12964-021-00721-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 02/10/2021] [Indexed: 02/06/2023] Open
Abstract
The circadian clock is an endogenous timekeeper system that controls and optimizes biological processes, which are consistent with a master circadian clock and peripheral clocks and are controlled by various genes. Notably, the disruption of circadian clock genes has been identified to affect a wide range of ailments, including cancers. The cancer-immunity cycle is composed of seven major steps, namely cancer cell antigen release and presentation, priming and activation of effector immunity cells, trafficking, and infiltration of immunity to tumors, and elimination of cancer cells. Existing evidence indicates that the circadian clock functions as a gate that govern many aspects of the cancer-immunity cycle. In this review, we highlight the importance of the circadian clock during tumorigenesis, and discuss the potential role of the circadian clock in the cancer-immunity cycle. A comprehensive understanding of the regulatory function of the circadian clock in the cancer-immunity cycle holds promise in developing new strategies for the treatment of cancer.
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