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Azimi M, Manavi MS, Afshinpour M, Khorram R, Vafadar R, Rezaei-Tazangi F, Arabzadeh D, Arabzadeh S, Ebrahimi N, Aref AR. Emerging immunologic approaches as cancer anti-angiogenic therapies. Clin Transl Oncol 2025; 27:1406-1425. [PMID: 39294514 DOI: 10.1007/s12094-024-03667-2] [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: 04/26/2024] [Accepted: 08/07/2024] [Indexed: 09/20/2024]
Abstract
Targeting tumor angiogenesis, the formation of new blood vessels supporting cancer growth and spread, has been an intense focus for therapy development. However, benefits from anti-angiogenic drugs like bevacizumab have been limited by resistance stemming from activation of compensatory pathways. Recent immunotherapy advances have sparked interest in novel immunologic approaches that can induce more durable vascular pruning and overcome limitations of existing angiogenesis inhibitors. This review comprehensively examines these emerging strategies, including modulating tumor-associated macrophages, therapeutic cancer vaccines, engineered nanobodies and T cells, anti-angiogenic cytokines/chemokines, and immunomodulatory drugs like thalidomide analogs. For each approach, the molecular mechanisms, preclinical/clinical data, and potential advantages over conventional drugs are discussed. Innovative therapeutic platforms like nanoparticle delivery systems are explored. Moreover, the importance of combining agents with distinct mechanisms to prevent resistance is evaluated. As tumors hijack angiogenesis for growth, harnessing the immune system's specificity to disrupt this process represents a promising anti-cancer strategy covered by this review.
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Affiliation(s)
- Mohammadreza Azimi
- Department of Biochemistry, Medical Faculty, Saveh Branch, Islamic Azad University, Saveh, Iran
| | | | - Maral Afshinpour
- Department of Chemistry and Biochemistry, South Dakota State University (SDSU), Brookings, SD, USA
| | - Roya Khorram
- Bone and Joint Diseases Research Center, Department of Orthopedic Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Vafadar
- Department of Orthopeadic Surgery, Kerman University of Medical Sciences, Kerman, Iran
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Danyal Arabzadeh
- Xi'an Jaiotong University Medical Campus, Xi'an Jaiotong University, Xi'an, Shaanxi Province, China
| | - Sattar Arabzadeh
- Xi'an Jaiotong University Medical Campus, Xi'an Jaiotong University, Xi'an, Shaanxi Province, China
| | - Nasim Ebrahimi
- Genetics Division, Department of Cell and Molecular Biology and Microbiology, Faculty of Science and Technology, University of Isfahan, Isfahan, Iran.
| | - Amir Reza Aref
- Mass General Cancer Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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2
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Bruni M, Lobefaro F, Pellegrini C, Mastrangelo M, Gualdi G, Esposito M, Antonetti P, De Sanctis P, Amerio P, Fargnoli MC. Psoriasis and cancer: the role of inflammation, immunosuppression, and cancer treatment. Expert Opin Biol Ther 2025; 25:395-411. [PMID: 40034077 DOI: 10.1080/14712598.2025.2471093] [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: 12/17/2024] [Revised: 02/10/2025] [Accepted: 02/19/2025] [Indexed: 03/05/2025]
Abstract
INTRODUCTION The relationship between psoriasis, immunomodulatory therapies, and the risk of malignancies is complex and still debated. The scarcity of evidence in this field makes clinicians hesitate to prescribe biological therapies for 'difficult-to-treat' patients. AREAS COVERED Based on a comprehensive MEDLINE/PUBMED search of articles published up to November 2024, this review synthesizes the current evidence on the association between psoriasis and cancer. This review specifically addresses four key aspects: the overall cancer risk in psoriatic patients, the potential role of cytokines involved in psoriasis pathogenesis in tumor development, the association between biological therapies and the incidence of new malignancies in this population, and the risk of cancer recurrence or progression in patients with a history of malignancy who are treated with biologics. EXPERT OPINION Biological therapies do not significantly elevate malignancy risk compared to non-biological treatments or the general population. Evidence is also reassuring for patients with prior malignancy, showing no tumor progression or recurrence. These findings support the timely use of biological treatments in 'difficult-to-treat' patients. Regular cancer screenings and risk-factor minimization should always be recommended for psoriatic patients undergoing immunomodulatory therapies. Multidisciplinary management involving oncologists is suggested, particularly for patients with active and advanced oncological disease.
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Affiliation(s)
- Manfredo Bruni
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Fabio Lobefaro
- Dermatology, Department of Medicine and Aging Science, University of Chieti-Pescara, Chieti, Italy
| | - Cristina Pellegrini
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Mirco Mastrangelo
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Giulio Gualdi
- Dermatology, Department of Medicine and Aging Science, University of Chieti-Pescara, Chieti, Italy
| | - Maria Esposito
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Paolo Antonetti
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Paolo De Sanctis
- Dermatology, Department of Medicine and Aging Science, University of Chieti-Pescara, Chieti, Italy
| | - Paolo Amerio
- Dermatology, Department of Medicine and Aging Science, University of Chieti-Pescara, Chieti, Italy
| | - Maria Concetta Fargnoli
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
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García-Domínguez M. The Role of IL-23 in the Development of Inflammatory Diseases. BIOLOGY 2025; 14:347. [PMID: 40282212 PMCID: PMC12025033 DOI: 10.3390/biology14040347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2025] [Revised: 03/23/2025] [Accepted: 03/25/2025] [Indexed: 04/29/2025]
Abstract
Interleukin-23 is crucial in the initiation and progression of certain inflammatory disorders. As a key cytokine, IL-23 is involved in the differentiation and activation of Th17 cells, which play a role in a broad spectrum of inflammatory diseases. This review examines the molecular mechanisms through which IL-23 contributes to the pathogenesis of conditions including psoriasis, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. By elucidating the significant role of IL-23 in inflammation, this review underscores its importance as a therapeutic target for managing inflammatory conditions, with particular emphasis on current and emerging biologic treatments.
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Affiliation(s)
- Mario García-Domínguez
- Program of Immunology and Immunotherapy, CIMA-Universidad de Navarra, 31008 Pamplona, Spain;
- Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
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Li Y, Wang W, Zhu R, Zhu X, Sun M, Huang Y, Chen W, Gao S, Jiao N, Lin X, Ke J, Xu T, Hou L, Lan P, Zhu L. STAT1 mediates the pro-inflammatory role of GBP5 in colitis. Commun Biol 2025; 8:385. [PMID: 40055493 PMCID: PMC11889220 DOI: 10.1038/s42003-025-07843-0] [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: 07/28/2024] [Accepted: 02/27/2025] [Indexed: 05/13/2025] Open
Abstract
Previous studies establish guanylate binding protein 5 (GBP5) as a driver in the development of inflammatory bowel diseases (IBDs). Here, we aim to elucidate the mechanism underlying the pro-inflammatory role of GBP5. We observe that loss of Gbp5 causes reduced colonic inflammation and decreased numbers of innate lymphoid cells (ILCs) in colitis mice. The transcriptional alterations observed in GBP5-deficient THP-1 cells mirrored those triggered by STAT1 activation, leading to the findings that GBP5 is essential for the stimulated expression of STAT1 and its downstream effectors, including cytokines that drive the expansion of ILCs. Remarkably, over-expression of STAT1 reverses the reduced cytokine expression caused by GBP5 deficiency. While GBP5 does not directly drive gene transcription, it binds with STAT1 and facilitates its nuclear translocation, thereby enhancing the expression of STAT1 itself and its downstream effectors. Overall, GBP5 plays a pro-inflammatory role in IBD by enhancing the activity and expression of STAT1.
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Affiliation(s)
- Yichen Li
- Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Medical College, Jiaying University, Meizhou, China
- Guangdong Institute of Gastroenterology; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases; Biomedical Innovation Center; Department of General Surgery, the Six Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wenxia Wang
- Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Guangdong Institute of Gastroenterology; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases; Biomedical Innovation Center; Department of General Surgery, the Six Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Ruixin Zhu
- The Shanghai Tenth People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
| | - Xinyue Zhu
- The Shanghai Tenth People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Mingwei Sun
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China
| | - Yanlan Huang
- School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
| | - Wanning Chen
- The Shanghai Tenth People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Sheng Gao
- The Shanghai Tenth People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Na Jiao
- State Key Laboratory of Genetic Engineering, Fudan Microbiome Center, School of Life Sciences, Fudan University, Shanghai, China
| | - Xutao Lin
- Guangdong Institute of Gastroenterology; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases; Biomedical Innovation Center; Department of General Surgery, the Six Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jia Ke
- Guangdong Institute of Gastroenterology; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases; Biomedical Innovation Center; Department of General Surgery, the Six Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Tao Xu
- Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Medical College, Jiaying University, Meizhou, China
| | - Linlin Hou
- School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, China.
| | - Ping Lan
- Guangdong Institute of Gastroenterology; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases; Biomedical Innovation Center; Department of General Surgery, the Six Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
| | - Lixin Zhu
- Guangdong Institute of Gastroenterology; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases; Biomedical Innovation Center; Department of General Surgery, the Six Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
- Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot, China.
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Aires I, Parada B, Ferreira R, Oliveira PA. Recent animal models of bladder cancer and their application in drug discovery: an update of the literature. Expert Opin Drug Discov 2025:1-21. [PMID: 39954010 DOI: 10.1080/17460441.2025.2465373] [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: 06/13/2024] [Revised: 12/29/2024] [Accepted: 02/07/2025] [Indexed: 02/17/2025]
Abstract
INTRODUCTION Bladder cancer presents a significant health problem worldwide, with environmental and genetic factors contributing to its incidence. Histologically, it can be classified as carcinoma in situ, non-muscle invasive and muscle-invasive carcinoma, each one with distinct genetic alterations impacting prognosis and response to therapy. While traditional transurethral resection is commonly performed in carcinoma in situ and non-muscle invasive carcinoma, it often fails to prevent recurrence or progression to more aggressive phenotypes, leading to the frequent need for additional treatment such as intravesical chemotherapy or immunotherapy. Despite the advances made in recent years, treatment options for bladder cancer are still lacking due to the complex nature of this disease. So, animal models may hold potential for addressing these limitations, because they not only allow the study of disease progression but also the evaluation of therapies and the investigation of drug repositioning. AREAS COVERED This review discusses the use of animal models over the past decade, highlighting key discoveries and discussing advantages and disadvantages for new drug discovery. EXPERT OPINION Over the past decade animal models have been employed to evaluate new mechanisms underlying the responses to standard therapies, aiming to optimize bladder cancer treatment. The authors propose that molecular engineering techniques and AI may hold promise for the future development of more precise and effective targeted therapies in bladder cancer.
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Affiliation(s)
- Inês Aires
- Department of Chemistry, University of Aveiro, Aveiro, Portugal
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, Vila Real, Portugal
| | - Belmiro Parada
- Coimbra Institute for Clinical and Biomedical, University of Coimbra, Coimbra, Portugal
| | - Rita Ferreira
- Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Paula A Oliveira
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, Vila Real, Portugal
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Ono R, Maeda K, Tanioka T, Isozaki T. Monocyte-derived Langerhans cells express Delta-like 4 induced by peptidoglycan and interleukin-4 mediated suppression. Front Immunol 2025; 16:1532620. [PMID: 40018044 PMCID: PMC11865044 DOI: 10.3389/fimmu.2025.1532620] [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: 11/22/2024] [Accepted: 01/30/2025] [Indexed: 03/01/2025] Open
Abstract
T cells contribute to immunotherapy and autoimmune pathogenesis and Langerhans cells (LCs) have a substantial ability to activate T cells. In vitro-generated monocyte-derived LCs (Mo-LCs) are useful models to study LC function in autoimmune diseases and to test future LC-based immunotherapies. Although dendritic cells (DCs) expressing high levels of Delta-like 4 (DLL4+ DCs), which is a member of the Notch ligand family, have greater ability than DLL4- DCs to activate T cells, the induction method of human DLL4+ DCs has yet to be determined. The aim of this study is to establish whether Mo-LCs express DLL4 and establish the induction method of antigen presenting cells, which most potently activate T cells, similar to our previously established induction method of human Mo-LCs. We compared the ratios of DLL4 expression and T cell activation via flow cytometry among monocyte-derived cells, which have a greater ability than the resident cells to activate T cells. Here, we discovered that Mo-LCs expressed DLL4, which most potently activated T cells among monocyte-derived cells, and that Mo-LCs and DLL4 expression were induced by DLL4, granulocyte macrophage colony-stimulating factor, and transforming growth factor-β1. Additionally, peptidoglycan was required for DLL4 expression, whereas interleukin-4 repressed it. These findings provide insights into the roles of DLL4-expressing cells such as DLL4+ Mo-LCs in human diseases, which will assist with the development of more effective therapeutic strategies in the future.
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Affiliation(s)
- Rei Ono
- Department of Pathogenesis and Translational Medicine, Showa University Graduate School of Pharmacy, Tokyo, Japan
| | - Kohei Maeda
- Department of Pathogenesis and Translational Medicine, Showa University Graduate School of Pharmacy, Tokyo, Japan
| | - Toshihiro Tanioka
- Department of Pathogenesis and Translational Medicine, Showa University Graduate School of Pharmacy, Tokyo, Japan
| | - Takeo Isozaki
- Department of Pathogenesis and Translational Medicine, Showa University Graduate School of Pharmacy, Tokyo, Japan
- Department of Rheumatology, Showa University Graduate School of Medicine, Tokyo, Japan
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García-Díaz N, Solli E, Hajjar E, Cornillot-Clément S, Landskron J, Ahmad R, Wei Q, Taskén K. MAPK and STAT3 Inhibitors Modulate FoxP3 Expression and Regulatory T Cell Function. Eur J Immunol 2025; 55:e202451225. [PMID: 39955647 DOI: 10.1002/eji.202451225] [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: 04/26/2024] [Revised: 01/29/2025] [Accepted: 01/30/2025] [Indexed: 02/17/2025]
Abstract
Regulatory T cells (Tregs) are a subset of T cells defined by the expression of Forkhead box protein P3 (FoxP3) playing a crucial role in regulating effector T cell activity. Tregs accumulate in the tumor microenvironment facilitating tumor growth. Thus, targeting FoxP3+ Tregs could improve cancer immunotherapies. Here, we conducted a high-throughput, phenotypic screening of a drug repurposing library to identify compounds downregulating FoxP3 expression in human primary T cells. We identified the tyrosine kinase inhibitor bosutinib and the STAT3 inhibitor nifuroxazide effectively downregulating FoxP3 expression. To identify more potent compounds, structural analogs of these two compounds were searched and validated. These analogs were found to reduce FoxP3 expression in a similar- or more potent manner than the original hits. All compounds inhibited Treg suppressive functions and reduced the expression of Treg activation markers. Importantly, bosutinib disrupted FAK and CaMKII signaling more potently in Tregs, whilst nifuroxazide and its analog NA16 targeted STAT3 protein levels more effectively in Tregs. Additionally, bosutinib and NA16 targeted effector Tregs more effectively than other Treg subsets. In summary, bosutinib, nifuroxazide, and their analogs inhibited FoxP3 expression, Treg suppressive abilities, and Treg activation effectively, which could serve as tools for the improvement of current cancer immunotherapies.
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Affiliation(s)
- Nuria García-Díaz
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Elise Solli
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Ehsan Hajjar
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Selma Cornillot-Clément
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Johannes Landskron
- Centre for Molecular Medicine, Nordic EMBL Partnership, University of Oslo, Oslo, Norway
| | - Rafi Ahmad
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Department of Biotechnology, University of Inland Norway, Hamar, Norway
| | - Qian Wei
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Kjetil Taskén
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- KG Jebsen Centre for B-cell Malignancies, University of Oslo, Oslo, Norway
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Dai S, Peng Y, Wang G, Chen C, Chen Q, Yin L, Yan H, Zhang K, Tu M, Lu Z, Wei J, Li Q, Wu J, Jiang K, Zhu Y, Miao Y. LIM domain only 7: a novel driver of immune evasion through regulatory T cell differentiation and chemotaxis in pancreatic ductal adenocarcinoma. Cell Death Differ 2025; 32:271-290. [PMID: 39143228 PMCID: PMC11803110 DOI: 10.1038/s41418-024-01358-7] [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: 04/02/2024] [Revised: 08/03/2024] [Accepted: 08/05/2024] [Indexed: 08/16/2024] Open
Abstract
With advancements in genomics and immunology, immunotherapy has emerged as a revolutionary strategy for tumor treatment. However, pancreatic ductal adenocarcinoma (PDAC), an immunologically "cold" tumor, exhibits limited responsiveness to immunotherapy. This study aimed to address the urgent need to uncover PDAC's immune microenvironment heterogeneity and identify the molecular mechanisms driving immune evasion. Using single-cell RNA sequencing datasets and spatial proteomics, we discovered LIM domain only 7 (LMO7) in PDAC cells as a previously unrecognized driver of immune evasion through Treg cell enrichment. LMO7 was positively correlated with infiltrating regulatory T cells (Tregs) and dysfunctional CD8+ T cells. A series of in vitro and in vivo experiments demonstrated LMO7's significant role in promoting Treg cell differentiation and chemotaxis while inhibiting CD8+ T cells and natural killer cell cytotoxicity. Mechanistically, LMO7, through its LIM domain, directly bound and promoted the ubiquitination and degradation of Foxp1. Foxp1 negatively regulated transforming growth factor-beta (TGF-β) and C-C motif chemokine ligand 5 (CCL5) expression by binding to sites 2 and I/III, respectively. Elevated TGF-β and CCL5 levels contribute to Treg cell enrichment, inducing immune evasion in PDAC. Combined treatment with TGF-β/CCL5 antibodies, along with LMO7 inhibition, effectively reversed immune evasion in PDAC, activated the immune response, and prolonged mouse survival. Therefore, this study identified LMO7 as a novel facilitator in driving immune evasion by promoting Treg cell enrichment and inhibiting cytotoxic effector functions. Targeting the LMO7-Foxp1-TGF-β/CCL5 axis holds promise as a therapeutic strategy for PDAC. Graphical abstract revealing LMO7 as a novel facilitator in driving immune evasion by promoting Tregs differentiation and chemotaxis, inducing CD8+ T/natural killer cells inhibition.
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Affiliation(s)
- Shangnan Dai
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, PR China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, PR China
| | - Yunpeng Peng
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, PR China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, PR China
| | - Guangfu Wang
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, PR China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, PR China
| | - Chongfa Chen
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, PR China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, PR China
- Pancreas Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China
| | - Qiuyang Chen
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, PR China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, PR China
| | - Lingdi Yin
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, PR China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, PR China
| | - Han Yan
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, PR China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, PR China
| | - Kai Zhang
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, PR China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, PR China
| | - Min Tu
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, PR China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, PR China
| | - Zipeng Lu
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, PR China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, PR China
| | - Jishu Wei
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, PR China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, PR China
| | - Qiang Li
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, PR China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, PR China
| | - Junli Wu
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, PR China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, PR China
| | - Kuirong Jiang
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, PR China
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, PR China
| | - Yi Zhu
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, PR China.
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, PR China.
| | - Yi Miao
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, PR China.
- Pancreas Institute, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, PR China.
- Pancreas Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China.
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Chang CF, Bao BY, Lu TL, Chen LC, Chen YT, Lin TP. Uncovering the Role of ALDH1A2 in Prostate Cancer: Insights from Genetic and Expression Analyses. J Cancer 2025; 16:932-941. [PMID: 39781359 PMCID: PMC11705053 DOI: 10.7150/jca.104705] [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: 10/05/2024] [Accepted: 12/14/2024] [Indexed: 01/12/2025] Open
Abstract
Biochemical recurrence (BCR) is a critical concern in prostate cancer management; however, its underlying genetic determinants remain poorly understood. The aldehyde dehydrogenase 1 (ALDH1) gene family is involved in cellular detoxification and biosynthetic processes and has been implicated in various cancers. This study investigated the association between the ALDH1 family members and prostate cancer recurrence. We conducted a two-stage genetic association study involving 134 single-nucleotide polymorphisms within the ALDH1 family to assess their association with BCR-free survival in prostate cancer. Gene set and pathway enrichment analyses were performed to explore the biological relevance of significant genes across multiple datasets. ALDH1A2 rs16939929 showed a robust association with BCR-free survival in both discovery and replication cohorts. Functional analyses indicated that rs16939929 affected ALDH1A2 expression in various tissues. Pooled analysis of 42 prostate cancer gene expression datasets revealed that ALDH1A2 expression was significantly lower in prostate cancer tissues and higher expression was associated with better patient prognosis. Enrichment analyses revealed that ALDH1A2 was co-expressed with genes primarily involved in cell adhesion pathways. Further analysis confirmed that several of these co-expressed cell adhesion molecules were associated with improved patient survival. In addition, ALDH1A2 expression was associated with increased immune cell infiltration into the prostate cancer microenvironment. In conclusion, ALDH1A2 rs16939929 is a significant predictor of BCR-free survival in prostate cancer, potentially through its effects on the gene expressions of ALDH1A2 and cell adhesion molecules. These findings suggest that ALDH1A2 plays a tumor-suppressive role in prostate cancer progression.
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Affiliation(s)
- Chi-Fen Chang
- Department of Anatomy, School of Medicine, China Medical University, Taichung 406, Taiwan
| | - Bo-Ying Bao
- Department of Pharmacy, China Medical University, Taichung 406, Taiwan
| | - Te-Ling Lu
- Department of Pharmacy, China Medical University, Taichung 406, Taiwan
| | - Lih-Chyang Chen
- Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan
| | - Yei-Tsung Chen
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Tzu-Ping Lin
- Department of Urology, College of Medicine and Shu-Tien Urological Research Center, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Department of Urology, Taipei Veterans General Hospital, Taipei 112, Taiwan
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10
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Brouwer MAE, Karami Z, Keating ST, Vrijmoeth H, Lemmers HLM, Dijkstra H, van de Veerdonk FL, Lupse M, Ter Hofstede HJM, Netea MG, Joosten LAB. Borrelia burgdorferi sensu lato inhibits CIITA transcription through pSTAT3 activation and enhanced SOCS1 and SOCS3 expression leading to limited IFN-γ production. Ticks Tick Borne Dis 2025; 16:102442. [PMID: 39879745 DOI: 10.1016/j.ttbdis.2025.102442] [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: 08/21/2024] [Revised: 12/30/2024] [Accepted: 01/13/2025] [Indexed: 01/31/2025]
Abstract
Interferons (IFNs) are important signaling molecules in the human immune response against micro-organisms. Throughout initial Borrelia burgdorferi sensu lato (B. burgdorferi s.l.) infection in vitro, inadequate IFN-γ production results in the absence of a strong T-helper 1 cell response, potentially hampering the development of an effective antibody responses in Lyme borreliosis (LB) patients. The aim of this study is to help understand the immunomodulatory mechanisms why IFN-γ production is absent in the early onset of LB. Therefore, cytokine production and STAT activation signature, following exposure of human immune cells to B. burgdorferi s.l., was investigated in vivo and in vitro. While STAT3 phosphorylation was highly induced in T cells, B cells and NK-(T) cells, STAT1 expression and IL-12p70 production were not or only slightly increased upon B. burgdorferi s.l. exposure. In response to B. burgdorferi s.l., STAT2 phosphorylation and IFNα production remained stable. STAT2 activation only increased in NK-(T) cells. In contrast, STAT4 signaling was reduced in all B. burgdorferi s.l. exposed immune cells. Moreover, B. burgdorferi s.l. significantly increased suppressor of cytokine signaling (SOCS)1 and SOCS3 gene expression in LB patients. Absence of IFN-γ production and STAT4 activation, in combination with STAT3 phosphorylation and upregulated SOCS1 and SOCS3 gene expression, suggests the formation of a more tolerant and anti-inflammatory response to B. burgdorferi s.l., specifically in T- and B-cells. In primary human PBMCs and monocyte populations, B. burgdorferi s.l. also specifically interfered with CIITA isoforms normally expressed in antigen presenting dendritic cells. In contrast, it enhanced CIITA isoforms typically present in adaptive immune cell subsets. Restoring antigen presentation capacity of innate immune cells and early production of IFN-γ in LB patients may help re-establish immune functions during initial LB. These new insights will help to understand the immunomodulatory mechanisms of B. burgdorferi s.l. during the onset of LB.
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Affiliation(s)
- Michelle A E Brouwer
- Department of Internal Medicine and Radboud Community for Infectious diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Zara Karami
- Department of Internal Medicine and Radboud Community for Infectious diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Samuel T Keating
- Department of Internal Medicine and Radboud Community for Infectious diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands; Department of Biology, University of Copenhagen, Copenhagen DK 2200, Denmark
| | - Hedwig Vrijmoeth
- Department of Internal Medicine and Radboud Community for Infectious diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Heidi L M Lemmers
- Department of Internal Medicine and Radboud Community for Infectious diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Helga Dijkstra
- Department of Internal Medicine and Radboud Community for Infectious diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Frank L van de Veerdonk
- Department of Internal Medicine and Radboud Community for Infectious diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Mihaela Lupse
- Department of Infectious Diseases, University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca 400349, Romania
| | - Hadewych J M Ter Hofstede
- Department of Internal Medicine and Radboud Community for Infectious diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Community for Infectious diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands; Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
| | - Leo A B Joosten
- Department of Internal Medicine and Radboud Community for Infectious diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands; Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
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11
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Lizana-Vasquez GD, Ramasubramanian S, Davarzani A, Cappabianca D, Saha K, Karumbaiah L, Torres-Lugo M. In Vitro Assessment of Thermo-Responsive Scaffold as a 3D Synthetic Matrix for CAR-T Potency Testing Against Glioblastoma Spheroids. J Biomed Mater Res A 2025; 113:e37823. [PMID: 39460647 DOI: 10.1002/jbm.a.37823] [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: 07/26/2024] [Revised: 09/13/2024] [Accepted: 10/14/2024] [Indexed: 10/28/2024]
Abstract
Chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated exceptional efficacy against hematological malignancies, but notably less against solid tumors. To overcome this limitation, it is critical to investigate antitumor CAR-T cell potency in synthetic 3D microenvironments that can simulate the physical barriers presented by solid tumors. The overall goal of this study was the preliminary assessment of a synthetic thermo-responsive material as a substrate for in vitro co-cultures of anti-disialoganglioside (GD2) CAR-T cells and patient-derived glioblastoma (GBM) spheroids. Independent co-culture experiments demonstrated that the encapsulation process did not adversely affect the cell cycle progression of glioma stem cells (GSCs) or CAR-T cells. GSC spheroids grew over time within the terpolymer scaffold, when seeded in the same ratio as the suspension control. Co-cultures of CAR-T cells in suspension with hydrogel-encapsulated GSC spheroids demonstrated that CAR-T cells could migrate through the hydrogel and target the encapsulated GSC spheroids. CAR-T cells killed approximately 80% of encapsulated GSCs, while maintaining effective CD4:CD8 T cell ratios and secreting inflammatory cytokines after interacting with GD2-expressing GSCs. Importantly, the scaffolds also facilitated cell harvesting for downstream cellular analysis. This study demonstrated that a synthetic 3D terpolymer hydrogel can serve as an artificial scaffold to investigate cellular immunotherapeutic potency against solid tumors.
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Affiliation(s)
- Gaby D Lizana-Vasquez
- Department of Chemical Engineering, University of Puerto Rico-Mayagüez, Mayagüez, Puerto Rico, USA
| | - Shanmathi Ramasubramanian
- Regenerative Bioscience Center, University of Georgia, Athens, Georgia, USA
- Edgar L. Rhodes Center for Animal and Dairy Science, College of Agriculture and Environmental Science, University of Georgia, Athens, Georgia, USA
| | - Amin Davarzani
- Regenerative Bioscience Center, University of Georgia, Athens, Georgia, USA
- School of Electrical and Computer Engineering, University of Georgia, Athens, Georgia, USA
| | - Dan Cappabianca
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Krishanu Saha
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Lohitash Karumbaiah
- Regenerative Bioscience Center, University of Georgia, Athens, Georgia, USA
- Edgar L. Rhodes Center for Animal and Dairy Science, College of Agriculture and Environmental Science, University of Georgia, Athens, Georgia, USA
- Division of Neuroscience, Biomedical and Translational Sciences Institute, University of Georgia, Athens, Georgia, USA
| | - Madeline Torres-Lugo
- Department of Chemical Engineering, University of Puerto Rico-Mayagüez, Mayagüez, Puerto Rico, USA
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12
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Zhang C, Huang R, Ren L, Martincuks A, Song J, Kortylewski M, Swiderski P, Forman SJ, Yu H. Local CpG- Stat3 siRNA treatment improves antitumor effects of immune checkpoint inhibitors. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102357. [PMID: 39618825 PMCID: PMC11605413 DOI: 10.1016/j.omtn.2024.102357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 10/04/2024] [Indexed: 12/11/2024]
Abstract
Immune checkpoint blockade (ICB) therapy has significantly benefited patients with several types of solid tumors and some lymphomas. However, many of the treated patients do not have a durable clinical response. It has been demonstrated that rescuing exhausted CD8+ T cells is required for ICB-mediated antitumor effects. We recently developed an immunostimulatory strategy based on silencing STAT3 while stimulating immune responses by CpG, a ligand for Toll-like receptor 9 (TLR9). The CpG-small interfering RNA (siRNA) conjugates efficiently enter immune cells, silencing STAT3 and activating innate immunity to enhance T cell-mediated antitumor immune responses. In the present study, we demonstrate that blocking STAT3 through locally delivered CpG-Stat3 siRNA enhances the efficacies of the systemic PD-1 and CTLA4 blockade against mouse A20 B cell lymphoma. In addition, locally delivered CpG-Stat3 siRNA combined with systemic administration of PD-1 antibody significantly augmented both local and systemic antitumor effects against mouse B16 melanoma tumors, with enhanced tumor-associated T cell activation. Furthermore, locally delivered CpG-Stat3 siRNA enhanced CD8+ T cell tumor infiltration and antitumor activity in a xenograft tumor model. Overall, our studies in both B cell lymphoma and melanoma mouse models demonstrate the potential of combinatory immunotherapy with CpG-Stat3 siRNA and checkpoint inhibitors as a therapeutic strategy for B cell lymphoma and melanoma.
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Affiliation(s)
- Chunyan Zhang
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Rui Huang
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Lyuzhi Ren
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Antons Martincuks
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA
| | - JiEun Song
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Marcin Kortylewski
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Piotr Swiderski
- DNA/RNA Synthesis Core Facility, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Stephen J. Forman
- Department of Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Hua Yu
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA
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13
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Krzysztofik M, Brzewski P, Kulbat A, Masajada M, Richter K, Wysocki WM. The IL-23/Th17 pathway inhibitors in the treatment of psoriasis and the risk of skin malignancies: a review. Postepy Dermatol Alergol 2024; 41:552-559. [PMID: 39877117 PMCID: PMC11770571 DOI: 10.5114/ada.2024.143428] [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: 07/25/2024] [Accepted: 08/03/2024] [Indexed: 01/31/2025] Open
Abstract
Psoriasis and psoriatic arthritis are chronic inflammatory conditions that constitute a significant global health burden due to their prevalence and impact on quality of life. A deeper comprehension of psoriasis and psoriatic arthritis pathogenesis has recently led to the emergence of novel classes of biologics targeting the IL-23/Th17 pathway. The specific role of interleukin-12, -23, and -17 in cancer as either promoters or inhibitors is under investigation in various studies. Here, we explore the potential role of interleukin-12, -23, and -17 in the development of skin tumours as well as the safety of using their inhibitors in the treatment of psoriasis and psoriatic arthritis, particularly in relation to the risk of melanoma and non-melanoma skin cancer (NMSC) development.
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Affiliation(s)
- Marta Krzysztofik
- Department of Dermatology and Venereology, Stefan Zeromski Municipal Hospital, Krakow, Poland
| | - Paweł Brzewski
- Department of Dermatology and Venereology, Stefan Zeromski Municipal Hospital, Krakow, Poland
- Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University, Krakow, Poland
| | - Aleksandra Kulbat
- Department of Oncological Surgery, 5 Military Clinical Hospital, Krakow, Poland
- National Institute of Oncology, Maria Sklodowska-Curie Memorial, Warsaw, Poland
| | - Magdalena Masajada
- Department of Dermatology and Venereology, Stefan Zeromski Municipal Hospital, Krakow, Poland
- Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University, Krakow, Poland
| | - Karolina Richter
- Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University, Krakow, Poland
| | - Wojciech M. Wysocki
- Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University, Krakow, Poland
- Department of Oncological Surgery, 5 Military Clinical Hospital, Krakow, Poland
- National Institute of Oncology, Maria Sklodowska-Curie Memorial, Warsaw, Poland
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14
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Wang H, Wang T, Yan S, Tang J, Zhang Y, Wang L, Xu H, Tu C. Crosstalk of pyroptosis and cytokine in the tumor microenvironment: from mechanisms to clinical implication. Mol Cancer 2024; 23:268. [PMID: 39614288 PMCID: PMC11607834 DOI: 10.1186/s12943-024-02183-9] [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: 07/13/2024] [Accepted: 11/22/2024] [Indexed: 12/01/2024] Open
Abstract
In the realm of cancer research, the tumor microenvironment (TME) plays a crucial role in tumor initiation and progression, shaped by complex interactions between cancer cells and surrounding non-cancerous cells. Cytokines, as essential immunomodulatory agents, are secreted by various cellular constituents within the TME, including immune cells, cancer-associated fibroblasts, and cancer cells themselves. These cytokines facilitate intricate communication networks that significantly influence tumor initiation, progression, metastasis, and immune suppression. Pyroptosis contributes to TME remodeling by promoting the release of pro-inflammatory cytokines and sustaining chronic inflammation, impacting processes such as immune escape and angiogenesis. However, challenges remain due to the complex interplay among cytokines, pyroptosis, and the TME, along with the dual effects of pyroptosis on cancer progression and therapy-related complications like cytokine release syndrome. Unraveling these complexities could facilitate strategies that balance inflammatory responses while minimizing tissue damage during therapy. This review delves into the complex crosstalk between cytokines, pyroptosis, and the TME, elucidating their contribution to tumor progression and metastasis. By synthesizing emerging therapeutic targets and innovative technologies concerning TME, this review aims to provide novel insights that could enhance treatment outcomes for cancer patients.
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Affiliation(s)
- Hua Wang
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Tao Wang
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Shuxiang Yan
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Jinxin Tang
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Yibo Zhang
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Liming Wang
- School of Biomedical Sciences, Hunan University, Changsha, Hunan, 410011, China.
| | - Haodong Xu
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
- Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
| | - Chao Tu
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
- Shenzhen Research Institute of Central South University, Guangdong, 518063, China.
- Hunan Engineering Research Center of AI Medical Equipment, The Second Xiangya Hospital of Central, South University, Changsha, Hunan, 410011, China.
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15
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He X, Liu P, Luo Y, Fu X, Yang T. STATs, promising targets for the treatment of autoimmune and inflammatory diseases. Eur J Med Chem 2024; 277:116783. [PMID: 39180944 DOI: 10.1016/j.ejmech.2024.116783] [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: 02/05/2024] [Revised: 08/14/2024] [Accepted: 08/16/2024] [Indexed: 08/27/2024]
Abstract
Cytokines play a crucial role in the pathophysiology of autoimmune and inflammatory diseases, with over 50 cytokines undergoing signal transduction through the Signal Transducers and Activators of Transcription (STAT) signaling pathway. Recent studies have solidly confirmed the pivotal role of STATs in autoimmune and inflammatory diseases. Therefore, this review provides a detailed summary of the immunological functions of STATs, focusing on exploring their mechanisms in various autoimmune and inflammatory diseases. Additionally, with the rapid advancement of structural biology in the field of drug discovery, many STAT inhibitors have been identified using structure-based drug design strategies. In this review, we also examine the structures of STAT proteins and compile the latest research on STAT inhibitors currently being tested in animal models and clinical trials for the treatment of immunological diseases, which emphasizes the feasibility of STATs as promising therapeutic targets and provides insights into the design of the next generation of STAT inhibitors.
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Affiliation(s)
- Xinlian He
- Laboratory of Human Diseases and Immunotherapy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Pingxian Liu
- Laboratory of Human Diseases and Immunotherapy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Youfu Luo
- Laboratory of Human Diseases and Immunotherapy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinyuan Fu
- Laboratory of Human Diseases and Immunotherapy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Tao Yang
- Laboratory of Human Diseases and Immunotherapy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China.
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16
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Wang Y, Xue L. Decoding the role of FOXP3 in esophageal cancer: Underlying mechanisms and therapeutic implications. Biochim Biophys Acta Rev Cancer 2024; 1879:189211. [PMID: 39532205 DOI: 10.1016/j.bbcan.2024.189211] [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: 06/12/2024] [Revised: 10/05/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024]
Abstract
Esophageal cancer is a significant contributor to cancer-related mortality, and its poor prognosis is primarily attributed to the aggressive nature of the tumor and challenges in early detection. Currently, there are no ideal drugs developed for treatment, making it crucial to explore potential biomarkers and molecular targets for esophageal cancer. FOXP3, as a transcription factor and major regulator of regulatory T cells, not only plays a role in promoting or inhibiting tumor development in various types of cancer cells including esophageal cancer cells but also influences the function of Treg cells by regulating the expression of multiple genes. This paper provides an in-depth discussion on the functional properties, regulatory mechanisms, key signaling pathways, as well as the role and potential application of FOXP3 in treating esophageal cancer. Furthermore, it comprehensively analyzes the complex role of this transcription factor within the tumor immune microenvironment with an aim to aid in developing new potential targets for esophageal cancer treatment.
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Affiliation(s)
- Yuanyuan Wang
- Department of Thoracic Surgery, Shanghai Changzheng Hospital, Second Affiliated Hospital of Naval Military Medical University, 200003 Shanghai, China.
| | - Lei Xue
- Department of Thoracic Surgery, Shanghai Changzheng Hospital, Second Affiliated Hospital of Naval Military Medical University, 200003 Shanghai, China.
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17
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Nouri N, Aghebati-Maleki L, Soltani-Zangbar MS, Kamrani A, Mehdizadeh A, Danaii S, Heris JA, Chakeri-Khiavi F, Yousefi M. Analysis of Th17 cell population and expression of microRNA and factors related to Th17 in patients with premature ovarian failure. J Reprod Immunol 2024; 165:104290. [PMID: 39053202 DOI: 10.1016/j.jri.2024.104290] [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: 09/27/2023] [Revised: 06/10/2024] [Accepted: 06/24/2024] [Indexed: 07/27/2024]
Abstract
Folliculogenesis is the process where follicles in the ovaries develop and eventually lead to ovulation. Any disruption to this process can cause premature ovarian failure. miR-326 is one of the microRNAs whose expression leads to Th17 production. Th17 activates the immune system to respond more vigorously, and by producing interlukins and cytokines causes inflammation and autoimmune disorders. Th17-induced inflammation and Th17/Treg imbalance can result in POF. This investigation took samples from 30 POF patients and 30 healthy people. The study utilized PCR to assess the expression levels of cytokines, specific transcription factor (ROR-γt), and miR-326. Additionally, ELISA was employed to analyze serum levels of IL-17, IL-21, IL-23. Furthermore, flow cytometry was utilized to determine the frequency of Th17. Compared to the control group, our results demonstrated a rise in the transcription factor RORɣt and a considerable rise in the frequency of Th17 cells in patients with POF. The level of inflammatory cytokines IL-17, IL-21, and IL-23 secreted in serum samples of patients with POF increased significantly compared to the control group. Results of investigating microRNA associated with Th17 cells also showed increased expression of miR-326 in females suffering from POF. The elevation of pro-inflammatory markers in women with POF contrary to the control group underscores the significant involvement of the immune system in pregnancy disorders pathogenesis. Consequently, immunological factors may serve as promising biomarkers for predicting POF likelihood in high-risk women in the future.
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Affiliation(s)
- Narjes Nouri
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mohammad Sadegh Soltani-Zangbar
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amin Kamrani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Mehdizadeh
- Hematology and Oncology Research Center,Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahla Danaii
- Gynecology Department, Eastern Azerbaijan ACECR ART center, Eastern Azerbaijan branch of ACECR, Tabriz, Iran
| | - Javad Ahmadian Heris
- Department of Allergy and Clinical Immunology, Pediatric Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mehdi Yousefi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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18
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Wang Z, Chang Y, Sun H, Li Y, Tang T. Advances in molecular mechanisms of inflammatory bowel disease‑associated colorectal cancer (Review). Oncol Lett 2024; 27:257. [PMID: 38646499 PMCID: PMC11027113 DOI: 10.3892/ol.2024.14390] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 03/15/2024] [Indexed: 04/23/2024] Open
Abstract
The link between inflammation and cancer is well documented and colonic inflammation caused by inflammatory bowel disease (IBD) is thought to be a high-risk factor for the development of colorectal cancer (CRC). The complex crosstalk between epithelial and inflammatory cells is thought to underlie the progression from inflammation to cancer. The present review collates and summarises recent advances in the understanding of the pathogenesis of IBD-associated CRC (IBD-CRC), including the oncogenic mechanisms of the main inflammatory signalling pathways and genetic alterations induced by oxidative stress during colonic inflammation, and discusses the crosstalk between the tumour microenvironment, intestinal flora and host immune factors during inflammatory oncogenesis in colitis-associated CRC. In addition, the therapeutic implications of anti-inflammatory therapy for IBD-CRC were discussed, intending to provide new insight into improve clinical practice.
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Affiliation(s)
- Zhi Wang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Yu Chang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Haibo Sun
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Yuqin Li
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Tongyu Tang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
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19
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Sobah ML, Liongue C, Ward AC. Stat3 Regulates Developmental Hematopoiesis and Impacts Myeloid Cell Function via Canonical and Non-Canonical Modalities. J Innate Immun 2024; 16:262-282. [PMID: 38643762 PMCID: PMC11249464 DOI: 10.1159/000538364] [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: 09/17/2023] [Accepted: 03/12/2024] [Indexed: 04/23/2024] Open
Abstract
INTRODUCTION Signal transducer and activator of transcription (STAT) 3 is extensively involved in the development, homeostasis, and function of immune cells, with STAT3 disruption associated with human immune-related disorders. The roles ascribed to STAT3 have been assumed to be due to its canonical mode of action as an inducible transcription factor downstream of multiple cytokines, although alternative noncanonical functional modalities have also been identified. The relative involvement of each mode was further explored in relevant zebrafish models. METHODS Genome editing with CRISPR/Cas9 was used to generate mutants of the conserved zebrafish Stat3 protein: a loss of function knockout (KO) mutant and a mutant lacking C-terminal sequences including the transactivation domain (ΔTAD). Lines harboring these mutations were analyzed with respect to blood and immune cell development and function in comparison to wild-type zebrafish. RESULTS The Stat3 KO mutant showed perturbation of hematopoietic lineages throughout primitive and early definitive hematopoiesis. Neutrophil numbers did not increase in response to lipopolysaccharide (LPS) or granulocyte colony-stimulating factor (G-CSF) and their migration was significantly diminished, the latter correlating with abrogation of the Cxcl8b/Cxcr2 pathway, with macrophage responses perturbed. Intriguingly, many of these phenotypes were not shared by the Stat3 ΔTAD mutant. Indeed, only neutrophil and macrophage development were disrupted in these mutants with responsiveness to LPS and G-CSF maintained, and neutrophil migration actually increased. CONCLUSION This study has identified roles for zebrafish Stat3 within hematopoietic stem cells impacting multiple lineages throughout primitive and early definitive hematopoiesis, myeloid cell responses to G-CSF and LPS and neutrophil migration. Many of these roles showed conservation, but notably several involved noncanonical modalities, providing additional insights for relevant diseases.
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Affiliation(s)
| | - Clifford Liongue
- School of Medicine, Deakin University, Geelong, VIC, Australia
- Institute of Mental and Physical Health and Clinical Translation (IMPACT), Deakin University, Geelong, VIC, Australia
| | - Alister C. Ward
- School of Medicine, Deakin University, Geelong, VIC, Australia
- Institute of Mental and Physical Health and Clinical Translation (IMPACT), Deakin University, Geelong, VIC, Australia
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20
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Guo Q, Jin Y, Chen X, Ye X, Shen X, Lin M, Zeng C, Zhou T, Zhang J. NF-κB in biology and targeted therapy: new insights and translational implications. Signal Transduct Target Ther 2024; 9:53. [PMID: 38433280 PMCID: PMC10910037 DOI: 10.1038/s41392-024-01757-9] [Citation(s) in RCA: 427] [Impact Index Per Article: 427.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 01/16/2024] [Accepted: 01/19/2024] [Indexed: 03/05/2024] Open
Abstract
NF-κB signaling has been discovered for nearly 40 years. Initially, NF-κB signaling was identified as a pivotal pathway in mediating inflammatory responses. However, with extensive and in-depth investigations, researchers have discovered that its role can be expanded to a variety of signaling mechanisms, biological processes, human diseases, and treatment options. In this review, we first scrutinize the research process of NF-κB signaling, and summarize the composition, activation, and regulatory mechanism of NF-κB signaling. We investigate the interaction of NF-κB signaling with other important pathways, including PI3K/AKT, MAPK, JAK-STAT, TGF-β, Wnt, Notch, Hedgehog, and TLR signaling. The physiological and pathological states of NF-κB signaling, as well as its intricate involvement in inflammation, immune regulation, and tumor microenvironment, are also explicated. Additionally, we illustrate how NF-κB signaling is involved in a variety of human diseases, including cancers, inflammatory and autoimmune diseases, cardiovascular diseases, metabolic diseases, neurological diseases, and COVID-19. Further, we discuss the therapeutic approaches targeting NF-κB signaling, including IKK inhibitors, monoclonal antibodies, proteasome inhibitors, nuclear translocation inhibitors, DNA binding inhibitors, TKIs, non-coding RNAs, immunotherapy, and CAR-T. Finally, we provide an outlook for research in the field of NF-κB signaling. We hope to present a stereoscopic, comprehensive NF-κB signaling that will inform future research and clinical practice.
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Affiliation(s)
- Qing Guo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yizi Jin
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xinyu Chen
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, PR China
| | - Xiaomin Ye
- Department of Cardiology, the First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China
| | - Xin Shen
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mingxi Lin
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Cheng Zeng
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Teng Zhou
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jian Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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21
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Wertheimer T, Zwicky P, Rindlisbacher L, Sparano C, Vermeer M, de Melo BMS, Haftmann C, Rückert T, Sethi A, Schärli S, Huber A, Ingelfinger F, Xu C, Kim D, Häne P, Fonseca da Silva A, Muschaweckh A, Nunez N, Krishnarajah S, Köhler N, Zeiser R, Oukka M, Korn T, Tugues S, Becher B. IL-23 stabilizes an effector T reg cell program in the tumor microenvironment. Nat Immunol 2024; 25:512-524. [PMID: 38356059 PMCID: PMC10907296 DOI: 10.1038/s41590-024-01755-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 01/12/2024] [Indexed: 02/16/2024]
Abstract
Interleukin-23 (IL-23) is a proinflammatory cytokine mainly produced by myeloid cells that promotes tumor growth in various preclinical cancer models and correlates with adverse outcomes. However, as to how IL-23 fuels tumor growth is unclear. Here, we found tumor-associated macrophages to be the main source of IL-23 in mouse and human tumor microenvironments. Among IL-23-sensing cells, we identified a subset of tumor-infiltrating regulatory T (Treg) cells that display a highly suppressive phenotype across mouse and human tumors. The use of three preclinical models of solid cancer in combination with genetic ablation of Il23r in Treg cells revealed that they are responsible for the tumor-promoting effect of IL-23. Mechanistically, we found that IL-23 sensing represents a crucial signal driving the maintenance and stabilization of effector Treg cells involving the transcription factor Foxp3. Our data support that targeting the IL-23/IL-23R axis in cancer may represent a means of eliciting antitumor immunity.
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Affiliation(s)
- Tobias Wertheimer
- Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Pascale Zwicky
- Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Lukas Rindlisbacher
- Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Colin Sparano
- Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Marijne Vermeer
- Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Bruno Marcel Silva de Melo
- Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
- Department of Pharmacology, Center for Research in Inflammatory Diseases, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil
| | - Claudia Haftmann
- Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Tamina Rückert
- Department of Internal Medicine I, Hematology, Oncology, and Stem Cell Transplantation, Faculty of Medicine, Medical Centre, University of Freiburg, Freiburg, Germany
| | - Aakriti Sethi
- Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Stefanie Schärli
- Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Anna Huber
- Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Florian Ingelfinger
- Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Caroline Xu
- Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Daehong Kim
- Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Philipp Häne
- Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - André Fonseca da Silva
- Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Andreas Muschaweckh
- Institute for Experimental Neuroimmunology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany
| | - Nicolas Nunez
- Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Sinduya Krishnarajah
- Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Natalie Köhler
- Department of Internal Medicine I, Hematology, Oncology, and Stem Cell Transplantation, Faculty of Medicine, Medical Centre, University of Freiburg, Freiburg, Germany
- Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, Freiburg, Germany
| | - Robert Zeiser
- Department of Internal Medicine I, Hematology, Oncology, and Stem Cell Transplantation, Faculty of Medicine, Medical Centre, University of Freiburg, Freiburg, Germany
- Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, Freiburg, Germany
| | - Mohamed Oukka
- Department of Immunology, University of Washington, Seattle, WA, USA
| | - Thomas Korn
- Institute for Experimental Neuroimmunology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Sonia Tugues
- Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
| | - Burkhard Becher
- Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
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22
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Liu J, Zhang B, Zhang G, Shang D. Reprogramming of regulatory T cells in inflammatory tumor microenvironment: can it become immunotherapy turning point? Front Immunol 2024; 15:1345838. [PMID: 38449875 PMCID: PMC10915070 DOI: 10.3389/fimmu.2024.1345838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 01/29/2024] [Indexed: 03/08/2024] Open
Abstract
Overcoming the immunosuppressive tumor microenvironment and identifying widely used immunosuppressants with minimal side effects are two major challenges currently hampering cancer immunotherapy. Regulatory T cells (Tregs) are present in almost all cancer tissues and play an important role in preserving autoimmune tolerance and tissue homeostasis. The tumor inflammatory microenvironment causes the reprogramming of Tregs, resulting in the conversion of Tregs to immunosuppressive phenotypes. This process ultimately facilitates tumor immune escape or tumor progression. However, current systemic Treg depletion therapies may lead to severe autoimmune toxicity. Therefore, it is crucial to understand the mechanism of Treg reprogramming and develop immunotherapies that selectively target Tregs within tumors. This article provides a comprehensive review of the potential mechanisms involved in Treg cell reprogramming and explores the application of Treg cell immunotherapy. The interference with reprogramming pathways has shown promise in reducing the number of tumor-associated Tregs or impairing their function during immunotherapy, thereby improving anti-tumor immune responses. Furthermore, a deeper understanding of the mechanisms that drive Treg cell reprogramming could reveal new molecular targets for future treatments.
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Affiliation(s)
- Jinming Liu
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Biao Zhang
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Guolin Zhang
- Department of Cardiology, The Second Hospital of Dalian Medical University, Dalian, China
| | - Dong Shang
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
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23
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Gershoni A, Hassin O, Nataraj NB, Baruch S, Avioz‐Seligman A, Pirona AC, Fellus‐Alyagor L, Meir Salame T, Mukherjee S, Mallel G, Yarden Y, Aylon Y, Oren M. TAZ facilitates breast tumor growth by promoting an immune-suppressive tumor microenvironment. Mol Oncol 2023; 17:2675-2693. [PMID: 37716913 PMCID: PMC10701768 DOI: 10.1002/1878-0261.13525] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 05/03/2023] [Accepted: 09/15/2023] [Indexed: 09/18/2023] Open
Abstract
The core Hippo pathway module consists of a tumour-suppressive kinase cascade that inhibits the transcriptional coactivators Yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1; also known as TAZ). When the Hippo pathway is downregulated, as often occurs in breast cancer, YAP/TAZ activity is induced. To elaborate the roles of TAZ in triple-negative breast cancer (TNBC), we depleted Taz in murine TNBC 4T1 cells, using either CRISPR/Cas9 or small hairpin RNA (shRNA). TAZ-depleted cells and their controls, harbouring wild-type levels of TAZ, were orthotopically injected into the mammary fat pads of syngeneic BALB/c female mice, and mice were monitored for tumour growth. TAZ depletion resulted in smaller tumours compared to the tumours generated by control cells, in line with the notion that TAZ functions as an oncogene in breast cancer. Tumours, as well as their corresponding in vitro cultured cells, were then subjected to gene expression profiling by RNA sequencing (RNA-seq). Interestingly, pathway analysis of the RNA-seq data indicated a TAZ-dependent enrichment of 'Inflammatory Response', a pathway correlated with TAZ expression levels also in human breast cancer tumours. Specifically, the RNA-seq analysis predicted a significant depletion of regulatory T cells (Tregs) in TAZ-deficient tumours, which was experimentally validated by the staining of tumour sections and by quantitative cytometry by time of flight (CyTOF). Strikingly, the differences in tumour size were completely abolished in immune-deficient mice, demonstrating that the immune-modulatory capacity of TAZ is critical for its oncogenic activity in this setting. Cytokine array analysis of conditioned medium from cultured cells revealed that TAZ increased the abundance of a small group of cytokines, including plasminogen activator inhibitor 1 (Serpin E1; also known as PAI-1), CCN family member 4 (CCN4; also known as WISP-1) and interleukin-23 (IL-23), suggesting a potential mechanistic explanation for its in vivo immunomodulatory effect. Together, our results imply that TAZ functions in a non-cell-autonomous manner to modify the tumour immune microenvironment and dampen the anti-tumour immune response, thereby facilitating tumour growth.
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Affiliation(s)
- Anat Gershoni
- Department of Molecular Cell BiologyWeizmann Institute of ScienceRehovotIsrael
| | - Ori Hassin
- Department of Molecular Cell BiologyWeizmann Institute of ScienceRehovotIsrael
| | | | - Sivan Baruch
- Department of Molecular Cell BiologyWeizmann Institute of ScienceRehovotIsrael
| | - Adi Avioz‐Seligman
- Department of Molecular Cell BiologyWeizmann Institute of ScienceRehovotIsrael
| | - Anna Chiara Pirona
- Department of Molecular Cell BiologyWeizmann Institute of ScienceRehovotIsrael
| | - Liat Fellus‐Alyagor
- Department of Veterinary ResourcesWeizmann Institute of ScienceRehovotIsrael
| | - Tomer Meir Salame
- Flow Cytometry Unit, Department of Life Sciences Core FacilitiesWeizmann Institute of ScienceRehovotIsrael
| | | | - Giuseppe Mallel
- Department of Molecular Cell BiologyWeizmann Institute of ScienceRehovotIsrael
| | - Yosef Yarden
- Department of Immunology and Regenerative BiologyWeizmann Institute of ScienceRehovotIsrael
| | - Yael Aylon
- Department of Molecular Cell BiologyWeizmann Institute of ScienceRehovotIsrael
| | - Moshe Oren
- Department of Molecular Cell BiologyWeizmann Institute of ScienceRehovotIsrael
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24
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Guo X, Wang Y, An Y, Liu Z, Liu J, Chen J, Zhan MM, Liang M, Hou Z, Wan C, Yin F, Wang R, Li Z. Development of Lysine Crotonyl-Mimic Probe to Covalently Identify H3K27Cr Interacting Proteins. Chemistry 2023; 29:e202301624. [PMID: 37587551 DOI: 10.1002/chem.202301624] [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: 05/22/2023] [Revised: 08/09/2023] [Accepted: 08/16/2023] [Indexed: 08/18/2023]
Abstract
Histone lysine crotonylation (Kcr) is one newly discovered acylation modification and regulates numerous pathophysiological processes. The binding affinity between Kcr and its interacting proteins is generally weak, which makes it difficult to effectively identify Kcr-interacting partners. Changing the amide of crotonyl to an ester increased reactivity with proximal cysteines and retained specificity for Kcr antibody. The probe "H3g27Cr" was designed by incorporating the ester functionality into a H3K27 peptide. Using this probe, multiple Kcr-interacting partners including STAT3 were successfully identified, and this has not been reported previously. Further experiments suggested that STAT3 possibly could form complexes with Histone deacetylase HDACs to downregulate the acetylation and crotonylation of Histone H3K27. Our unique design provided intriguing tools to further explore Kcr-interacting proteins and elucidate their working mechanisms.
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Affiliation(s)
- Xiaochun Guo
- State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, P.R. China
| | - Yuena Wang
- State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, P.R. China
| | - Yuhao An
- Pingshan translational medicine center, Shenzhen Bay Laboratory, Shenzhen, 518118, P.R. China
| | - Zhihong Liu
- Pingshan translational medicine center, Shenzhen Bay Laboratory, Shenzhen, 518118, P.R. China
| | - Jianbo Liu
- Pingshan translational medicine center, Shenzhen Bay Laboratory, Shenzhen, 518118, P.R. China
| | - Jiaxin Chen
- Pingshan translational medicine center, Shenzhen Bay Laboratory, Shenzhen, 518118, P.R. China
| | - Mei-Miao Zhan
- State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, P.R. China
| | - Mingcha Liang
- Pingshan translational medicine center, Shenzhen Bay Laboratory, Shenzhen, 518118, P.R. China
| | - Zhanfeng Hou
- State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, P.R. China
| | - Chuan Wan
- State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, P.R. China
| | - Feng Yin
- Pingshan translational medicine center, Shenzhen Bay Laboratory, Shenzhen, 518118, P.R. China
| | - Rui Wang
- Pingshan translational medicine center, Shenzhen Bay Laboratory, Shenzhen, 518118, P.R. China
| | - Zigang Li
- State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, P.R. China
- Pingshan translational medicine center, Shenzhen Bay Laboratory, Shenzhen, 518118, P.R. China
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25
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Yuan S, Zhu T, Wang J, Jiang R, Shu A, Zhang Z, Zhang P, Feng X, Zhao L. miR-22 promotes immunosuppression via activating JAK/STAT3 signaling in cutaneous squamous cell carcinoma. Carcinogenesis 2023; 44:549-561. [PMID: 37466677 DOI: 10.1093/carcin/bgad055] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/14/2023] [Accepted: 07/18/2023] [Indexed: 07/20/2023] Open
Abstract
Immunotherapy is the only approved systemic therapy for advanced cutaneous squamous cell carcinoma (cSCC), however, roughly 50% of patients do not respond to the therapy and resistance often occurs over time to those who initially respond. Immunosuppression could have a critical role in developing treatment resistance, thus, understanding the mechanisms of how immunosuppression is developed and regulated may be the key to improving clinical diagnosis and treatment strategies for cSCC. Here, through using a series of immunocompetent genetically engineered mouse models, we demonstrate that miR-22 promotes cSCC development by establishing regulatory T cells (Tregs)-mediated immunosuppressive tumor microenvironment (TME) in a tumor cell autonomous manner. Mechanism investigation revealed that miR-22 elicits the constitutive activation of JAK/STAT3 signaling by directly targeting its suppressor SOCS3, which augments cancer cell-derived chemokine secretion and Tregs recruitment. Epithelial-specific and global knockouts of miR-22 repress papilloma and cSCC development and progression, manifested with reduced Tregs infiltration and elevated CD8+ T cell activation. Transcriptomic analysis and functional rescue study confirmed CCL17, CCL20 and CCL22 as the main affected chemokines that mediate the chemotaxis between miR-22 highly expressing keratinocyte tumor cells and Tregs. Conversely, overexpression of SOCS3 reversed miR-22-induced Tregs recruitment toward tumor cells. Clinically, gradually increasing Tregs infiltration during cSCC progression was negatively correlated with SOCS3 abundance, supported by previously documented elevated miR-22 levels. Thus, our study uncovers a novel miR-22-SOCS3-JAK/STAT3-chemokines regulatory mechanism in defining the immunosuppressive TME and highlights the promising clinical application value of miR-22 as a common targeting molecule against JAK/STAT3 signaling and immune escape in cSCC.
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Affiliation(s)
- Shukai Yuan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China
| | - Tong Zhu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China
| | - Jianan Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China
| | - Ruoyu Jiang
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin 300052, China
| | - Aofeng Shu
- School of Basic Medicine, Xinxiang Medical University, Xinxiang 453003, China
| | - Zhenlei Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China
| | - Peitao Zhang
- Department of Nuclear Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin 300052, China
| | - Xuequan Feng
- Neurosurgical Department, Tianjin First Central Hospital, No. 24 Fukang Road, Nankai District, Tianjin 300192, China
| | - Li Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China
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26
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Tan J, Feng R. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors. Open Med (Wars) 2023; 18:20230792. [PMID: 37724127 PMCID: PMC10505358 DOI: 10.1515/med-2023-0792] [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: 09/04/2022] [Revised: 03/30/2023] [Accepted: 08/08/2023] [Indexed: 09/20/2023] Open
Abstract
Combined cancer immunotherapy and targeted therapy have proven to be effective against various cancers and therefore have recently become the focus of cancer research. Signal transducer and activator of transcription 3 (STAT3) is a member of the STAT protein family of transcription factors. Several studies have shown that STAT3 can affect the prognosis of cancer patients by regulating immune microenvironment (IME). Therefore, STAT3 may have high research value for the development of combined immunotherapy/targeted therapy approaches for the treatment of cancer patients. We found differences in STAT3 expression between tumor and normal tissues. Kaplan-Meier survival and Cox regression analyses showed that high expression of STAT3 is associated with poor prognosis in low-grade glioma (LGG) patients. The results of the analysis of the area under the curve of the receiver operating characteristic curve further suggested that the expression of STAT3 is an effective way to evaluate the prognosis of patients with glioma. The results of the IME analysis revealed that the immune and matrix scores of LGGs were positively correlated with the expression of STAT3 (P < 0.05). The results of immune cell infiltration analysis showed that STAT3 was positively correlated with resting dendritic cells, eosinophils, neutrophils, M0 macrophages, M1 macrophages, CD4 memory resting T cells, and CD8 T cells in LGG patients, but negatively correlated with activated mast cells and M2 macrophages (P < 0.05). Our gene set enrichment analysis identified 384 enriched pathways. According to the enrichment scores, the top ten most significantly upregulated pathways were related to immune response. The top ten most significantly downregulated pathways were related to cell signal transduction and the regulation of cell survival, proliferation, and metabolism. Genetic alteration analysis showed that missense mutations in STAT3 account for the majority of mutations, and STAT3 mutations mostly occur in the Src homology domain. In conclusion overexpression of STAT3 can promote the development and growth of tumors by regulating IME, which is significantly related to the poor prognosis of cancer patients. Therefore, targeted inhibition of STAT3 expression may have high research value for the development of combined immunotherapy/targeted therapy approaches for the treatment of cancer patients.
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Affiliation(s)
- Junyin Tan
- Department of Oncology, Guigang People’s Hospital of Guangxi/The Eighth Affiliated Hospital of Guangxi Medical University, Guigang, Guangxi, China
| | - Ronghao Feng
- Department of Oncology, Guigang People’s Hospital of Guangxi/The Eighth Affiliated Hospital of Guangxi Medical University, Guigang, Guangxi, China
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27
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Craig S, Stretch C, Farshidfar F, Sheka D, Alabi N, Siddiqui A, Kopciuk K, Park YJ, Khalil M, Khan F, Harvey A, Bathe OF. A clinically useful and biologically informative genomic classifier for papillary thyroid cancer. Front Endocrinol (Lausanne) 2023; 14:1220617. [PMID: 37772080 PMCID: PMC10523308 DOI: 10.3389/fendo.2023.1220617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 08/22/2023] [Indexed: 09/30/2023] Open
Abstract
Clinical management of papillary thyroid cancer depends on estimations of prognosis. Standard care, which relies on prognostication based on clinicopathologic features, is inaccurate. We applied a machine learning algorithm (HighLifeR) to 502 cases annotated by The Cancer Genome Atlas Project to derive an accurate molecular prognostic classifier. Unsupervised analysis of the 82 genes that were most closely associated with recurrence after surgery enabled the identification of three unique molecular subtypes. One subtype had a high recurrence rate, an immunosuppressed microenvironment, and enrichment of the EZH2-HOTAIR pathway. Two other unique molecular subtypes with a lower rate of recurrence were identified, including one subtype with a paucity of BRAFV600E mutations and a high rate of RAS mutations. The genomic risk classifier, in addition to tumor size and lymph node status, enabled effective prognostication that outperformed the American Thyroid Association clinical risk stratification. The genomic classifier we derived can potentially be applied preoperatively to direct clinical decision-making. Distinct biological features of molecular subtypes also have implications regarding sensitivity to radioactive iodine, EZH2 inhibitors, and immune checkpoint inhibitors.
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Affiliation(s)
- Steven Craig
- Department of Surgery, Illawarra Shoalhaven Local Health District, Wollongong, NSW, Australia
- Graduate School of Medicine, University of Wollongong, Wollongong, NSW, Australia
| | - Cynthia Stretch
- Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Farshad Farshidfar
- Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Dropen Sheka
- Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Nikolay Alabi
- Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Ashar Siddiqui
- O’Brien Centre for the Bachelor of Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Karen Kopciuk
- Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Cancer Epidemiology and Prevention Research, Alberta Health Services, Calgary, AB, Canada
| | - Young Joo Park
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea
| | - Moosa Khalil
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Faisal Khan
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- OncoHelix, Calgary, AB, Canada
| | - Adrian Harvey
- Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Oliver F. Bathe
- Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Research and Development, Qualisure Diagnostics Inc., Calgary, AB, Canada
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28
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Khanolkar A, Liu G, Simpson Schneider BM. Defining the Basal and Immunomodulatory Mediator-Induced Phosphoprotein Signature in Pediatric B Cell Acute Lymphoblastic Leukemia (B-ALL) Diagnostic Samples. Int J Mol Sci 2023; 24:13937. [PMID: 37762241 PMCID: PMC10531382 DOI: 10.3390/ijms241813937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/29/2023] [Accepted: 08/31/2023] [Indexed: 09/29/2023] Open
Abstract
It is theorized that dysregulated immune responses to infectious insults contribute to the development of pediatric B-ALL. In this context, our understanding of the immunomodulatory-mediator-induced signaling responses of leukemic blasts in pediatric B-ALL diagnostic samples is rather limited. Hence, in this study, we defined the signaling landscape of leukemic blasts, as well as normal mature B cells and T cells residing in diagnostic samples from 63 pediatric B-ALL patients. These samples were interrogated with a range of immunomodulatory-mediators within 24 h of collection, and phosflow analyses of downstream proximal signaling nodes were performed. Our data reveal evidence of basal hyperphosphorylation across a broad swath of these signaling nodes in leukemic blasts in contrast to normal mature B cells and T cells in the same sample. We also detected similarities in the phosphoprotein signature between blasts and mature B cells in response to IFNγ and IL-2 treatment, but significant divergence in the phosphoprotein signature was observed between blasts and mature B cells in response to IL-4, IL-7, IL-10, IL-21 and CD40 ligand treatment. Our results demonstrate the existence of both symmetry and asymmetry in the phosphoprotein signature between leukemic and non-leukemic cells in pediatric B-ALL diagnostic samples.
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Affiliation(s)
- Aaruni Khanolkar
- Department of Pathology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA
- Department of Pathology, Northwestern University, Chicago, IL 60611, USA
| | - Guorong Liu
- Department of Pathology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA
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Sisto M, Lisi S. Interleukin-23 Involved in Fibrotic Autoimmune Diseases: New Discoveries. J Clin Med 2023; 12:5699. [PMID: 37685766 PMCID: PMC10489062 DOI: 10.3390/jcm12175699] [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: 08/03/2023] [Revised: 08/29/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023] Open
Abstract
Interleukin (IL)-23 is a central pro-inflammatory cytokine with a broad range of effects on immune responses. IL-23 is pathologically linked to the induction of the production of the pro-inflammatory cytokines IL-17 and IL-22, which stimulate the differentiation and proliferation of T helper type 17 (Th17) cells. Recent discoveries suggest a potential pro-fibrotic role for IL-23 in the development of chronic inflammatory autoimmune diseases characterized by intense fibrosis. In this review, we summarized the biological features of IL-23 and gathered recent research on the role of IL-23 in fibrotic autoimmune conditions, which could provide a theoretical basis for clinical targeting and drug development.
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Affiliation(s)
- Margherita Sisto
- Department of Translational Biomedicine and Neuroscience (DiBraiN), Section of Human Anatomy and Histology, University of Bari “Aldo Moro”, 70123 Bari, Italy;
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30
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Zhang C, Huang R, Ren L, Song J, Kortylewski M, Swiderski P, Forman S, Yu H. Local CpG- Stat3 siRNA treatment improves antitumor effects of immune checkpoint inhibitors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.17.553571. [PMID: 37645787 PMCID: PMC10462083 DOI: 10.1101/2023.08.17.553571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
Immune checkpoint blockade (ICB) therapy has significantly benefited patients with several types of solid tumors and some lymphomas. However, many of the treated patients do not have durable clinical response. It has been demonstrated that rescuing exhausted CD8 + T cells is required for ICB-mediated antitumor effects. We recently developed an immunostimulatory strategy based on silencing STAT3 while stimulating immune responses by CpG, ligand for Toll-like receptor 9 (TLR9). The CpG-small interfering RNA (siRNA) conjugates efficiently enter immune cells, silencing STAT3 and activating innate immunity to enhance T-cell mediated antitumor immune responses. In the present study, we demonstrate that blocking STAT3 through locally delivered CpG- Stat3 siRNA enhances the efficacies of the systemic PD-1 and CTLA4 blockade against mouse A20 B cell lymphoma. In addition, locally delivered CpG- Stat3 siRNA combined with systemic administration of PD-1 antibody significantly augmented both local and systemic antitumor effects against mouse B16 melanoma tumors, with enhanced tumor-associated T cell activation. Overall, our studies in both B cell lymphoma and melanoma mouse models demonstrate the potential of combinatory immunotherapy with CpG- Stat3 siRNA and checkpoint inhibitors as a therapeutic strategy for B cell lymphoma and melanoma.
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31
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Cai X, Rong R, Huang Y, Pu X, Ge N. Effects of theophylline combined with inhaled corticosteroids on patients with moderate and severe asthma and changes of T lymphocyte subsets in peripheral blood. Cent Eur J Immunol 2023; 48:135-143. [PMID: 37692023 PMCID: PMC10485692 DOI: 10.5114/ceji.2023.127843] [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: 10/12/2022] [Accepted: 03/29/2023] [Indexed: 09/12/2023] Open
Abstract
Introduction Asthma is a common respiratory disease. Theophylline combined with inhaled corticosteroids (ICS) is a promising therapy for asthma. This study explored the therapeutic effects of ICS combined with theophylline on moderate and severe asthma patients and T lymphocyte subsets (CD3+CD8+ T cells) in peripheral blood. Material and methods A total of 202 moderate and severe asthma patients were selected, with 101 treated with theophylline combined with ICS and 101 treated with ICS alone as controls. Lung function [forced expiratory volume within 1 second (FEV1), forced vital capacity (FVC), and peak expiratory flow (PEF)] were tested using a spirometer. Asthma symptom control was evaluated by asthma control tests (ACT). The life quality was evaluated using the Asthma Quality of Life Questionnaire (AQLQ). The number and percentage of CD3+ T, CD3+CD4+ T and CD3+CD8+ T cells in peripheral blood mononuclear cells were assessed by flow cytometry. The correlation between CD3+CD8+ T cells and lung function and asthma control of patients after combination therapy was analyzed by Pearson correlation analysis. Results Compared with moderate and severe patients treated with ICS alone, theophylline improved the efficacy of ICS. Theophylline combined with ICS decreased IL-4 and IL-6 levels, and CD3+ T and CD3+CD8+ T cell number and percentage. After combined treatment, CD3+ CD8+ T cells in peripheral blood of patients were positively correlated with lung function and negatively correlated with asthma control. Conclusions The additional use of theophylline improved the efficacy of corticosteroids in asthma patient treatment and reduced inflammation level and CD3+ T and CD3+CD8+ T cell contents in peripheral blood.
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Affiliation(s)
- Xiaozhen Cai
- Department of Respiratory and Critical Care Medicine, Houjie Hospital Affiliated to Guangdong Medical University, Dongguan, Guangdong, China
| | - Rong Rong
- Department of Respiratory and Critical Care Medicine, Houjie Hospital Affiliated to Guangdong Medical University, Dongguan, Guangdong, China
| | - Yidan Huang
- Department of Respiratory and Critical Care Medicine, Houjie Hospital Affiliated to Guangdong Medical University, Dongguan, Guangdong, China
| | - Xiaowen Pu
- Department of Respiratory and Critical Care Medicine, Houjie Hospital Affiliated to Guangdong Medical University, Dongguan, Guangdong, China
| | - Nanhai Ge
- Department of Respiratory and Critical Care Medicine, Houjie Hospital Affiliated to Guangdong Medical University, Dongguan, Guangdong, China
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Matuszczak S, Szczepanik K, Grządziel A, Drzyzga A, Cichoń T, Czapla J, Pilny E, Smolarczyk R. The Effect of Radiotherapy on Cell Survival and Inflammatory Cytokine and Chemokine Secretion in a Co-Culture Model of Head and Neck Squamous Cell Carcinoma and Normal Cells. Biomedicines 2023; 11:1773. [PMID: 37371868 DOI: 10.3390/biomedicines11061773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 06/01/2023] [Accepted: 06/19/2023] [Indexed: 06/29/2023] Open
Abstract
Radiotherapy (RT) is one of the main treatments for head and neck squamous cell carcinomas (HNSCCs). Unfortunately, radioresistance is observed in many cases of HNSCCs. The effectiveness of RT depends on both the direct effect inducing cell death and the indirect effect of changing the tumor microenvironment (TME). Knowledge of interactions between TME components after RT may help to design a new combined treatment with RT. In the study, we investigated the effect of RT on cell survival and cell secretion in a co-culture model of HNSCCs in vitro. We examined changes in cell proliferation, colony formation, cell cycle phases, type of cell death, cell migration and secretion after irradiation. The obtained results suggest that the presence of fibroblasts and endothelial cells in co-culture with HNSCCs inhibits the function of cell cycle checkpoints G1/S and G2/M and allows cells to enter the next phase of the cell cycle. We showed an anti-apoptotic effect in co-culture of HNSCCs with fibroblasts or endothelial cells in relation to the execution phase of apoptosis, although we initially observed increased activation of the early phase of apoptosis in the co-cultures after irradiation. We hypothesize that the anti-apoptotic effect depends on increased secretion of IL-6 and MCP-1.
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Affiliation(s)
- Sybilla Matuszczak
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland
| | - Krzysztof Szczepanik
- Radiotherapy Department, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland
| | - Aleksandra Grządziel
- Radiotherapy Planning Department, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland
| | - Alina Drzyzga
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland
| | - Tomasz Cichoń
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland
| | - Justyna Czapla
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland
| | - Ewelina Pilny
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland
| | - Ryszard Smolarczyk
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland
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Wang LW, Ruan H, Wang BM, Qin Y, Zhong WL. Microbiota regulation in constipation and colorectal cancer. World J Gastrointest Oncol 2023; 15:776-786. [PMID: 37275451 PMCID: PMC10237018 DOI: 10.4251/wjgo.v15.i5.776] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/23/2023] [Accepted: 04/21/2023] [Indexed: 05/12/2023] Open
Abstract
The relevance of constipation to the development and progression of colorectal cancer (CRC) is currently a controversial issue. Studies have shown that changes in the composition of the gut microbiota, a condition known as ecological imbalance, are correlated with an increasing number of common human diseases, including CRC and constipation. CRC is the second leading cause of cancer-related deaths worldwide, and constipation has been receiving widespread attention as a risk factor for CRC. Early colonoscopy screening of constipated patients, with regular follow-ups and timely intervention, can help detect early intestinal lesions and reduce the risks of developing colorectal polyps and CRC. As an important regulator of the intestinal microenvironment, the gut microbiota plays a critical role in the onset and progression of CRC. An increasing amount of evidence supports the thought that gut microbial composition and function are key determinants of CRC development and progression, with alterations inducing changes in the expression of host genes, metabolic regulation, and local and systemic immunological responses. Furthermore, constipation greatly affects the composition of the gut microbiota, which in turn influences the susceptibility to intestinal diseases such as CRC. However, the crosstalk between the gut microbiota, constipation, and CRC is still unclear.
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Affiliation(s)
- Li-Wei Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Hao Ruan
- China Resources Biopharmaceutical Company Limited, Beijing 100029, China
| | - Bang-Mao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Yuan Qin
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
| | - Wei-Long Zhong
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
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34
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Maryam S, Krukiewicz K, Haq IU, Khan AA, Yahya G, Cavalu S. Interleukins (Cytokines) as Biomarkers in Colorectal Cancer: Progression, Detection, and Monitoring. J Clin Med 2023; 12:jcm12093127. [PMID: 37176567 PMCID: PMC10179696 DOI: 10.3390/jcm12093127] [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: 03/18/2023] [Revised: 04/18/2023] [Accepted: 04/20/2023] [Indexed: 05/15/2023] Open
Abstract
Cancer is the primary cause of death in economically developed countries and the second leading cause in developing countries. Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide. Risk factors for CRC include obesity, a diet low in fruits and vegetables, physical inactivity, and smoking. CRC has a poor prognosis, and there is a critical need for new diagnostic and prognostic biomarkers to reduce related deaths. Recently, studies have focused more on molecular testing to guide targeted treatments for CRC patients. The most crucial feature of activated immune cells is the production and release of growth factors and cytokines that modulate the inflammatory conditions in tumor tissues. The cytokine network is valuable for the prognosis and pathogenesis of colorectal cancer as they can aid in the cost-effective and non-invasive detection of cancer. A large number of interleukins (IL) released by the immune system at various stages of CRC can act as "biomarkers". They play diverse functions in colorectal cancer, and include IL-4, IL-6, IL-8, IL-11, IL-17A, IL-22, IL-23, IL-33, TNF, TGF-β, and vascular endothelial growth factor (VEGF), which are pro-tumorigenic genes. However, there are an inadequate number of studies in this area considering its correlation with cytokine profiles that are clinically useful in diagnosing cancer. A better understanding of cytokine levels to establish diagnostic pathways entails an understanding of cytokine interactions and the regulation of their various biochemical signaling pathways in healthy individuals. This review provides a comprehensive summary of some interleukins as immunological biomarkers of CRC.
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Affiliation(s)
- Sajida Maryam
- Department of Biosciences, COMSATS University Islamabad (CUI), Islamabad 44000, Pakistan
| | - Katarzyna Krukiewicz
- Department of Physical Chemistry and Technology of Polymers, Silesian University of Technology, M. Strzody 9, 44-100 Gliwice, Poland
- Centre for Organic and Nanohybrid Electronics, Silesian University of Technology, Konarskiego 22B, 44-100 Gliwice, Poland
| | - Ihtisham Ul Haq
- Department of Biosciences, COMSATS University Islamabad (CUI), Islamabad 44000, Pakistan
- Department of Physical Chemistry and Technology of Polymers, Silesian University of Technology, M. Strzody 9, 44-100 Gliwice, Poland
- Joint Doctoral School, Silesian University of Technology, Akademicka 2A, 44-100 Gliwice, Poland
| | - Awal Ayaz Khan
- Department of Biosciences, COMSATS University Islamabad (CUI), Islamabad 44000, Pakistan
| | - Galal Yahya
- Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Al Sharqia, Egypt
- Department of Molecular Genetics, Faculty of Biology, Technical University of Kaiserslautern, Paul-Ehrlich Str. 24, 67663 Kaiserslautern, Germany
| | - Simona Cavalu
- Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, 410087 Oradea, Romania
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Ochman B, Mielcarska S, Kula A, Dawidowicz M, Robotycka J, Piecuch J, Szrot M, Dzięgielewska-Gęsiak S, Muc-Wierzgoń M, Waniczek D, Świętochowska E. Do Elevated YKL-40 Levels Drive the Immunosuppressive Tumor Microenvironment in Colorectal Cancer? Assessment of the Association of the Expression of YKL-40, MMP-8, IL17A, and PD-L1 with Coexisting Type 2 Diabetes, Obesity, and Active Smoking. Curr Issues Mol Biol 2023; 45:2781-2797. [PMID: 37185706 PMCID: PMC10136442 DOI: 10.3390/cimb45040182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/23/2023] [Accepted: 03/24/2023] [Indexed: 03/29/2023] Open
Abstract
The influence of chitinase-3-like protein 1 (YKL-40 or CHI3L1) expression on the immunological properties of the tumor microenvironment, which may affect the effectiveness of immunotherapy, is currently not sufficiently understood in colorectal cancer (CRC). The aim of this study was to investigate the relationship between YKL-40 expression and the immunological properties of the tumor microenvironment in CRC. We performed in silico analysis, including analysis of immune cell infiltration scores and the immune landscape depending on YKL-40 expression, gene set enrichment analysis (GSEA), and analysis of three Gene Expression Omnibus (GEO) datasets. In 48 CRC tissue homogenates and the surgical margin, we analyzed the expression of YKL-40, MMP8, IL17A, and PD-L1. Moreover, we analyzed the expression of YKL-40 in tissue homogenates retrieved from patients with coexisting diabetes, obesity, and smoking. The expression of YKL-40 was significantly higher in CRC tumor tissue compared to healthy tissue and correlated with MMP-8, IL17A, and PD-L1 expression. In silico analysis revealed an association of YKL-40 with disease recurrence, and GSEA revealed a potential link between elevated YKL-40 expression and immunosuppressive properties of the tumor microenvironment in CRC.
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36
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Fur removal promotes an earlier expression of involution-related genes in mammary gland of lactating mice. J Comp Physiol B 2023; 193:171-192. [PMID: 36650338 PMCID: PMC9992052 DOI: 10.1007/s00360-023-01474-9] [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: 09/22/2022] [Revised: 12/31/2022] [Accepted: 01/06/2023] [Indexed: 01/19/2023]
Abstract
Peak lactation occurs when milk production is at its highest. The factors limiting peak lactation performance have been subject of intense debate. Milk production at peak lactation appears limited by the capacity of lactating females to dissipate body heat generated as a by-product of processing food and producing milk. As a result, manipulations that enhance capacity to dissipate body heat (such as fur removal) increase peak milk production. We investigated the potential correlates of shaving-induced increases in peak milk production in laboratory mice. By transcriptomic profiling of the mammary gland, we searched for the mechanisms underlying experimentally increased milk production and its consequences for mother-young conflict over weaning, manifested by advanced or delayed involution of mammary gland. We demonstrated that shaving-induced increases in milk production were paradoxically linked to reduced expression of some milk synthesis-related genes. Moreover, the mammary glands of shaved mice had a gene expression profile indicative of earlier involution relative to unshaved mice. Once provided with enhanced capacity to dissipate body heat, shaved mice were likely to rear their young to independence faster than unshaved mothers.
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37
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Sun Y, Yu D, Geng X, Ding D, Yang Y, Liu Z, Xiao Z, Wang R, Tan W. Artificial Base-Directed In Vivo Assembly of an Albumin-siRNA Complex for Tumor-Targeting Delivery. ACS APPLIED MATERIALS & INTERFACES 2023; 15:8872-8883. [PMID: 36751121 DOI: 10.1021/acsami.2c19075] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
RNA interference (RNAi) mediated by short interfering RNA (siRNA) is a promising method for cancer treatment, but the clinical application is hampered by several limitations, including metabolic instability, lack of tumor specificity, and poor cellular uptake. To meet these challenges, we have explored the possibility of structure modification of siRNA with artificial bases for property optimization. A series of siRNAs functionalized with different numbers of hydrophobic base F are prepared for screening. The interactions of plasma proteins with F-base-modified siRNA (F-siRNA) are investigated, and it is identified that the interaction with serum albumin is dominant. Experiments revealed that the introduction of F bases conferred modified siRNA with improved tumor-specific accumulation, prolonged circulatory retention time, and better tissue permeability. Mechanistic studies indicated that the F base induces the formulation of a stable siRNA-albumin complex, which transports siRNA to tumor tissues selectively owing to an enhanced permeability and retention (EPR) effect of albumin. The F base also facilitates the binding of siRNA to transport-associated proteins on the cell membrane, enabling its cellular internalization. Together, these data demonstrate that F base modification confers siRNA-enhanced cellular uptake and biostability and specific accumulation in tumor tissue, which provides a new approach for the development of siRNA-based cancer therapeutics.
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Affiliation(s)
- Yang Sun
- Institute of Molecular Medicine (IMM), Renji Hospital, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Die Yu
- Institute of Molecular Medicine (IMM), Renji Hospital, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Xinyao Geng
- Institute of Molecular Medicine (IMM), Renji Hospital, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Ding Ding
- Institute of Molecular Medicine (IMM), Renji Hospital, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Yu Yang
- Institute of Molecular Medicine (IMM), Renji Hospital, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Zhuang Liu
- Institute of Functional Nano & Soft Materials Laboratory (FUNSOM), Soochow University, Suzhou 215123, Jiangsu, China
| | - Zeyu Xiao
- Institute of Molecular Medicine (IMM), Renji Hospital, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Ruowen Wang
- Institute of Molecular Medicine (IMM), Renji Hospital, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Weihong Tan
- Institute of Molecular Medicine (IMM), Renji Hospital, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha 410082, Hunan, China
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), The Chinese Academy of Sciences, Hangzhou 310022, Zhejiang, China
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Yang L, Zhao Q, Wang X, Pilapong C, Li Y, Zou J, Jin J, Rong J. Investigation on the regulatory T cells signature and relevant Foxp3/STAT3 axis in esophageal cancer. Cancer Med 2023; 12:4993-5008. [PMID: 36226375 PMCID: PMC9972178 DOI: 10.1002/cam4.5194] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 08/05/2022] [Accepted: 08/14/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Regulatory T cells (Tregs) have an important role in accelerating the immunosuppression of tumor. Tregs regulation is a hopeful strategy to improve the dismal prognosis of Esophageal cancer (EC), while its mechanisms have not yet been fully clarified. METHODS To characterize the role of Tregs in EC, we comprehensively explored its prognostic value, clinical pathology partnership, related biological functions and potential mechanisms at transcriptome level. Through the integrated analysis of GEO and TCGA datasets, we comprehensively evaluated the Tregs infiltration patterns in EC patients. The correlation between Tregs infiltration and genomic characteristics, as well as biological functions were analyzed by a variety of computational algorithms. RESULTS We observed that Tregs were significantly upregulated in EC and involved in various immune processes. According to TCGA and GEO transcriptional classification schemes, Tregs specific genes were observed to be highly expressed in tumor samples, as well as were closely associated with poor prognosis and worse clinical outcomes. In addition, EC patients can be stratified into high-risk and low-risk immune subgroups according to Tregs/macrophages infiltration level, and the results showed significant differences in tumor development, biological processes and probe gene expression pattern. The multi-variate analysis revealed that the interaction between STAT3 and Foxp3 was a potential prognostic signature of Tregs in EC, especially the modulation effect of STAT3 on Foxp3 expression, which has not been well studied in EC. We also identified that STAT3 and Foxp3 expression presented a high accuracy in predicting Tregs infiltration level in EC patients (AUC: 0.817; 95% CI: 0.756-0.878). CONCLUSIONS Our results revealed that Tregs have the potential to predict prognosis and tumor deterioration in EC patients. A comprehensive landscape of Tregs regulation mechanisms will help us interpret the immunosuppression of tumor microenvironment (TME) and novel strategies for EC immunotherapy.
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Affiliation(s)
- Lin Yang
- Department of Oncology, The Second People's Hospital of Yibin, Yibin, People's Republic of China.,Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Qijie Zhao
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.,Center of Excellence for Molecular Imaging (CEMI), Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | - Xing Wang
- Shichuan Nursing Vocational College, Chengdu, People's Republic of China
| | - Chalermchai Pilapong
- Center of Excellence for Molecular Imaging (CEMI), Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | - Yi Li
- Department of Oncology, The Second People's Hospital of Yibin, Yibin, People's Republic of China
| | - Jun Zou
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Jing Jin
- Department of Oncology, The Second People's Hospital of Yibin, Yibin, People's Republic of China
| | - Jinfeng Rong
- Department of Oncology, The Second People's Hospital of Yibin, Yibin, People's Republic of China
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Goswami S, Anandhan S, Raychaudhuri D, Sharma P. Myeloid cell-targeted therapies for solid tumours. Nat Rev Immunol 2023; 23:106-120. [PMID: 35697799 DOI: 10.1038/s41577-022-00737-w] [Citation(s) in RCA: 109] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/12/2022] [Indexed: 02/04/2023]
Abstract
Myeloid cells are the most abundant immune components of the tumour microenvironment, where they have a variety of functions, ranging from immunosuppressive to immunostimulatory roles. The myeloid cell compartment comprises many different cell types, including monocytes, macrophages, dendritic cells and granulocytes, that are highly plastic and can differentiate into diverse phenotypes depending on cues received from their microenvironment. In the past few decades, we have gained a better appreciation of the complexity of myeloid cell subsets and how they are involved in tumour progression and resistance to cancer therapies, including immunotherapy. In this Review, we highlight key features of monocyte and macrophage biology that are being explored as potential targets for cancer therapies and what aspects of myeloid cells need a deeper understanding to identify rational combinatorial strategies to improve clinical outcomes of patients with cancer. We discuss therapies that aim to modulate the functional activities of myeloid cell populations, impacting their recruitment, survival and activity in the tumour microenvironment, acting at the level of cell surface receptors, signalling pathways, epigenetic machinery and metabolic regulators. We also describe advances in the development of genetically engineered myeloid cells for cancer therapy.
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Affiliation(s)
- Sangeeta Goswami
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Swetha Anandhan
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,MD Anderson UT Health Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Deblina Raychaudhuri
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Padmanee Sharma
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. .,Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. .,The Immunotherapy Platform, The University of Texas MD Anderson Cancer, Center, Houston, TX, USA.
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Huseni MA, Wang L, Klementowicz JE, Yuen K, Breart B, Orr C, Liu LF, Li Y, Gupta V, Li C, Rishipathak D, Peng J, Şenbabaoǧlu Y, Modrusan Z, Keerthivasan S, Madireddi S, Chen YJ, Fraser EJ, Leng N, Hamidi H, Koeppen H, Ziai J, Hashimoto K, Fassò M, Williams P, McDermott DF, Rosenberg JE, Powles T, Emens LA, Hegde PS, Mellman I, Turley SJ, Wilson MS, Mariathasan S, Molinero L, Merchant M, West NR. CD8 + T cell-intrinsic IL-6 signaling promotes resistance to anti-PD-L1 immunotherapy. Cell Rep Med 2023; 4:100878. [PMID: 36599350 PMCID: PMC9873827 DOI: 10.1016/j.xcrm.2022.100878] [Citation(s) in RCA: 79] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 10/14/2022] [Accepted: 12/08/2022] [Indexed: 01/05/2023]
Abstract
Although immune checkpoint inhibitors (ICIs) are established as effective cancer therapies, overcoming therapeutic resistance remains a critical challenge. Here we identify interleukin 6 (IL-6) as a correlate of poor response to atezolizumab (anti-PD-L1) in large clinical trials of advanced kidney, breast, and bladder cancers. In pre-clinical models, combined blockade of PD-L1 and the IL-6 receptor (IL6R) causes synergistic regression of large established tumors and substantially improves anti-tumor CD8+ cytotoxic T lymphocyte (CTL) responses compared with anti-PD-L1 alone. Circulating CTLs from cancer patients with high plasma IL-6 display a repressed functional profile based on single-cell RNA sequencing, and IL-6-STAT3 signaling inhibits classical cytotoxic differentiation of CTLs in vitro. In tumor-bearing mice, CTL-specific IL6R deficiency is sufficient to improve anti-PD-L1 activity. Thus, based on both clinical and experimental evidence, agents targeting IL-6 signaling are plausible partners for combination with ICIs in cancer patients.
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Affiliation(s)
| | - Lifen Wang
- Genentech, South San Francisco, CA 94080, USA
| | | | - Kobe Yuen
- Genentech, South San Francisco, CA 94080, USA
| | | | | | - Li-Fen Liu
- Genentech, South San Francisco, CA 94080, USA
| | - Yijin Li
- Genentech, South San Francisco, CA 94080, USA
| | | | - Congfen Li
- Genentech, South San Francisco, CA 94080, USA
| | | | - Jing Peng
- Genentech, South San Francisco, CA 94080, USA
| | | | | | | | | | | | | | - Ning Leng
- Genentech, South San Francisco, CA 94080, USA
| | | | | | - James Ziai
- Genentech, South San Francisco, CA 94080, USA
| | | | | | | | | | - Jonathan E Rosenberg
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Thomas Powles
- Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
| | - Leisha A Emens
- University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA 15213, USA
| | | | - Ira Mellman
- Genentech, South San Francisco, CA 94080, USA
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Zhang Z, Bahaji Azami NL, Liu N, Sun M. Research Progress of Intestinal Microecology in the Pathogenesis of Colorectal Adenoma and Carcinogenesis. Technol Cancer Res Treat 2023; 22:15330338221135938. [PMID: 36740990 PMCID: PMC9903042 DOI: 10.1177/15330338221135938] [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: 06/19/2022] [Revised: 09/22/2022] [Accepted: 10/13/2022] [Indexed: 02/07/2023] Open
Abstract
Colorectal adenoma is a precancerous lesion that may progress to colorectal cancer. Patients with colorectal adenoma had a 4-fold higher risk of developing colorectal malignancy than the rest of the population, with approximately 80% of colorectal cancer originating from colorectal adenoma. Therefore, preventing the occurrence and progression of colorectal adenoma is crucial in reducing the risk for colorectal cancer. The human intestinal microecology is a complex system consisting of numerous microbial communities with a sophisticated structure. Interactions among intestinal microorganisms play crucial roles in maintaining normal intestinal structure, digestion, absorption, metabolism, and other functions. The colorectal system is the largest microbial bank or fermentation system in the human body. Studies suggest that intestinal microecological imbalance, one of the most important environmental factors, may play an essential role in the occurrence and development of colorectal adenoma and colorectal cancer. Based on the complexity of studying the gut microbiota ecosystem, its specific role in the occurrence and development of colorectal adenoma is yet to be elucidated. In addition, further studies are expected to provide new insights regarding the prevention and treatment of colorectal adenoma. This article reviews the relationship and mechanism of the diversity of the gut microbiota, the relevant inflammatory response, immune regulation, and metabolic changes in the presence of colorectal adenomas.
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Affiliation(s)
- Zhipeng Zhang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Nisma Lena Bahaji Azami
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ningning Liu
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mingyu Sun
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Khadela A, Shah Y, Mistry P, Bodiwala K, CB A. Immunomodulatory Therapy in Head and Neck Squamous Cell Carcinoma: Recent Advances and Clinical Prospects. Technol Cancer Res Treat 2023; 22:15330338221150559. [PMID: 36683526 PMCID: PMC9893386 DOI: 10.1177/15330338221150559] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
The immune system plays a significant role in the development, invasion, progression, and metastasis of head and neck cancer. Over the last decade, the emergence of immunotherapy has irreversibly altered the paradigm of cancer treatment. The current treatment modalities for head and neck squamous cell carcinoma (HNSCC) include surgery, radiotherapy, and adjuvant or neoadjuvant chemotherapy which has failed to provide satisfactory clinical outcomes. To encounter this, there is a need for a novel or targeted therapy such as immunological targets along with conventional treatment strategy for optimal therapeutic outcomes. The immune system can contribute to promoting metastasis, angiogenesis, and growth by exploiting the tumor's influence on the microenvironment. Immunological targets have been found effective in recent clinical studies and have shown promising results. This review outlines the important immunological targets and the medications acting on them that have already been explored, are currently under clinical trials and are further being targeted.
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Affiliation(s)
- Avinash Khadela
- Department of Pharmacology, L. M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat, India
| | - Yesha Shah
- Department of Pharmacology, L. M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat, India
| | - Priya Mistry
- Department of Pharmacology, L. M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat, India
| | - Kunjan Bodiwala
- Department of Pharmaceutical chemistry, L. M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat, India
| | - Avinash CB
- Medical Oncologist, ClearMedi Radiant Hospital, Mysore, India
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43
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Hu Q, Bian Q, Rong D, Wang L, Song J, Huang HS, Zeng J, Mei J, Wang PY. JAK/STAT pathway: Extracellular signals, diseases, immunity, and therapeutic regimens. Front Bioeng Biotechnol 2023; 11:1110765. [PMID: 36911202 PMCID: PMC9995824 DOI: 10.3389/fbioe.2023.1110765] [Citation(s) in RCA: 125] [Impact Index Per Article: 62.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 02/13/2023] [Indexed: 02/25/2023] Open
Abstract
Janus kinase/signal transduction and transcription activation (JAK/STAT) pathways were originally thought to be intracellular signaling pathways that mediate cytokine signals in mammals. Existing studies show that the JAK/STAT pathway regulates the downstream signaling of numerous membrane proteins such as such as G-protein-associated receptors, integrins and so on. Mounting evidence shows that the JAK/STAT pathways play an important role in human disease pathology and pharmacological mechanism. The JAK/STAT pathways are related to aspects of all aspects of the immune system function, such as fighting infection, maintaining immune tolerance, strengthening barrier function, and cancer prevention, which are all important factors involved in immune response. In addition, the JAK/STAT pathways play an important role in extracellular mechanistic signaling and might be an important mediator of mechanistic signals that influence disease progression, immune environment. Therefore, it is important to understand the mechanism of the JAK/STAT pathways, which provides ideas for us to design more drugs targeting diseases based on the JAK/STAT pathway. In this review, we discuss the role of the JAK/STAT pathway in mechanistic signaling, disease progression, immune environment, and therapeutic targets.
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Affiliation(s)
- Qian Hu
- Department of Pharmacy, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.,Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, China.,Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
| | - Qihui Bian
- Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, China
| | - Dingchao Rong
- Department of Orthopaedic Surgery, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Leiyun Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.,Department of Pharmacy, Wuhan First Hospital, Wuhan, China
| | - Jianan Song
- Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, China
| | - Hsuan-Shun Huang
- Department of Research, Center for Prevention and Therapy of Gynecological Cancers, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
| | - Jun Zeng
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Jie Mei
- Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, China.,Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
| | - Peng-Yuan Wang
- Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, China
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Tian Y, Liu H, Wang M, Wang R, Yi G, Zhang M, Chen R. Role of STAT3 and NRF2 in Tumors: Potential Targets for Antitumor Therapy. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27248768. [PMID: 36557902 PMCID: PMC9781355 DOI: 10.3390/molecules27248768] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/02/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022]
Abstract
Signal transducer and activator of transcription 3 (STAT3) and nuclear factor erythroid-derived 2-like 2 (NRF2, also known as NFE2L2), are two of the most complicated transcription regulators, which participate in a variety of physiological processes. Numerous studies have shown that they are overactivated in multiple types of tumors. Interestingly, STAT3 and NRF2 can also interact with each other to regulate tumor progression. Hence, these two important transcription factors are considered key targets for developing a new class of antitumor drugs. This review summarizes the pivotal roles of the two transcription regulators and their interactions in the tumor microenvironment to identify potential antitumor drug targets and, ultimately, improve patients' health and survival.
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Affiliation(s)
- Yanjun Tian
- Medical Laboratory of Jining Medical University, Jining Medical University, Jining 272067, China
| | - Haiqing Liu
- Department of Physiology, School of Basic Medical Sciences (Institute of Basic Medical Sciences), Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250024, China
| | - Mengwei Wang
- School of Stomatology, Jining Medical University, Jining 272067, China
| | - Ruihao Wang
- School of Mental Health, Jining Medical University, Jining 272067, China
| | - Guandong Yi
- School of Nursing, Jining Medical University, Jining 272067, China
| | - Meng Zhang
- Medical Laboratory of Jining Medical University, Jining Medical University, Jining 272067, China
| | - Ruijiao Chen
- Medical Laboratory of Jining Medical University, Jining Medical University, Jining 272067, China
- Correspondence: ; Tel.: +86-537-361-6216
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Teng L, Li Z, Shi Y, Gao Z, Yang Y, Wang Y, Bi L. Development and validation of a microenvironment-related prognostic model for hepatocellular carcinoma patients based on histone deacetylase family. Transl Oncol 2022; 26:101547. [PMID: 36191460 PMCID: PMC9531286 DOI: 10.1016/j.tranon.2022.101547] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 05/25/2022] [Accepted: 09/26/2022] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Histone deacetylase (HDAC) family can remove acetyl groups from histone lysine residues, and their high expression is closely related to the poor prognosis of hepatocellular carcinoma (HCC) patients. Recently, it has been reported to play an immunosuppressive role in the microenvironment, but little is known about the mechanism. METHODS Through machine learning, we trained and verified the prognostic model composed of HDACs. CIBERSORT was used to calculate the percentage of immune cells in the microenvironment. Based on co-expression network, potential targets of HDACs were screened. After that, qRT-PCR was employed to evaluate the expression of downstream genes of HDACs, while HPLC-CAD analysis was applied to detect the concentration of arachidonic acid (AA). Finally, Flow cytometry, WB and IHC experiments were used to detect CD86 expression in RAW246.7. RESULTS We constructed a great prognostic model composed of HDAC1 and HDAC11 that was significantly associated with overall survival. These HDACs were related to the abundance of macrophages, which might be attributed to their regulation of fatty-acid-metabolism related genes. In vitro experiments, the mRNA expression of ACSM2A, ADH1B, CYP2C8, CYP4F2 and SLC27A5 in HCC-LM3 was significantly down-regulated, and specific inhibitors of HDAC1 and HDAC11 significantly promoted the expression of these genes. HDAC inhibitors can promote the metabolism of AA, which may relieve the effect of AA on the polarization of M1 macrophages. CONCLUSIONS Our study revealed the blocking effect of HDAC1 and HDAC11 on the polarization of macrophages M1 in the microenvironment by inhibiting fatty acid metabolism.
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Affiliation(s)
- Linxin Teng
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu 210023, China; Jiangsu Provincial Engineering Research Center of TCM External Medication Development and Application, Nanjing 210023, China
| | - Zhengjun Li
- College of Health Economics Management, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu 210023, China; Jiangsu Provincial Engineering Research Center of TCM External Medication Development and Application, Nanjing 210023, China
| | - Yipeng Shi
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu 210023, China
| | - Zihan Gao
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu 210023, China
| | - Yang Yang
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu 210023, China
| | - Yunshan Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, 247 Beiyuan Street, Jinan, Shandong 250033, China
| | - Lei Bi
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu 210023, China; Jiangsu Provincial Engineering Research Center of TCM External Medication Development and Application, Nanjing 210023, China.
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Li W, An N, Wang M, Liu X, Mei Z. Interleukin-23 receptor defines T helper 1-like regulatory T cells in oral squamous cell carcinoma. Immun Inflamm Dis 2022; 10:e746. [PMID: 36444617 PMCID: PMC9682469 DOI: 10.1002/iid3.746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 10/26/2022] [Accepted: 11/08/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND The immune responses play significant roles in the onset, progression, and outcome of oral squamous cell carcinoma (OSCC). CD4+ regulatory T cells (Tregs) significantly impact tumor immunity. However, their role in OSCC development remains elusive. METHODS In a carcinogen-induced mouse OSCC model, interleukin-23 receptor (IL-23R) expression on Tregs and Treg function were determined by flow cytometry. IL-23R overexpression in Tregs was achieved by lentiviral infection, followed by evaluation of the expression of Forkhead box P3 (Foxp3), T-bet, retineic-acid-receptor-related orphan nuclear receptor gamma t, and cytokines by flow cytometry. Adoptive transfer assays were applied to analyze the function of IL-23R- overexpressing Tregs in vivo. The cellular sources of IL-23 were also determined by flow cytometry. RESULTS IL-23R- Tregs and IL-23R+ Tregs were found in the tongues but not spleens of OSCC-bearing mice. IL-23R+ Tregs expressed lower Foxp3 but higher T-bet than IL-23R- Tregs. IL-23R- Tregs produced abundant IL-10 and transforming growth factor (TGF)-β, while IL-23R+ Tregs produced lower IL-10 and TGF-β but remarkably higher interferon (IFN)-γ. Furthermore, IL-23R+ Tregs possessed more phosphorylated signal transducer and activator of transcription (STAT3) and STAT4 than IL-23R- Tregs. IL-23R+ Tregs were less immunosuppressive than IL-23R- Tregs, as evidenced by weaker inhibition of activated conventional T cells. IL-23R overexpression in splenic Tregs remarkably reduced the expression of IL-10 and TGF-β but increased IFN-γ expression when Tregs were adoptively transferred into OSCC-bearing mice. In the OSCC microenvironment, macrophages, dendritic cells, and malignant OSCC cells produced IL-23 which might modulate the function of IL-23R+ Tregs. CONCLUSIONS This study unveils Treg heterogeneity, thus deepening the understanding of Treg biology and tumor immunity in OSCC.
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Affiliation(s)
- Wei Li
- Department of Head and Neck Surgery, Hubei Cancer Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Ning An
- Department of Head and Neck Surgery, Hubei Cancer Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Mingwei Wang
- Department of Pathology, Hubei Cancer Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xiguo Liu
- Department of Head and Neck Surgery, Hubei Cancer Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Zhidan Mei
- Department of Head and Neck Surgery, Hubei Cancer Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
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Huang L, Peng S, Liu Z, Zhang J, Liu N, Lin J. Natural blood plasma-based hydrogels as tumor vaccines delivery systems to enhance biomimetic recruitment of antigen presenting cells for tumor immunotherapy. Mater Today Bio 2022; 17:100497. [DOI: 10.1016/j.mtbio.2022.100497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 11/13/2022] [Accepted: 11/15/2022] [Indexed: 11/18/2022] Open
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Wu Z, Lei K, Li H, He J, Shi E. Transcriptome-based network analysis related to M2-like tumor-associated macrophage infiltration identified VARS1 as a potential target for improving melanoma immunotherapy efficacy. J Transl Med 2022; 20:489. [PMID: 36303162 PMCID: PMC9615154 DOI: 10.1186/s12967-022-03686-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 09/23/2022] [Accepted: 10/02/2022] [Indexed: 11/10/2022] Open
Abstract
RATIONALE The M2-like tumor-associated macrophages (TAMs) are independent prognostic factors in melanoma. METHODS We performed weighted gene co-expression network analysis (WGCNA) to identify the module most correlated with M2-like TAMs. The Cancer Genome Atlas (TCGA) patients were classified into two clusters that differed based on prognosis and biological function, with consensus clustering. A prognostic model was established based on the differentially expressed genes (DEGs) of the two clusters. We investigated the difference in immune cell infiltration and immune response-related gene expression between the high and low risk score groups. RESULTS The risk score was defined as an independent prognostic value in melanoma. VARS1 was a hub gene in the M2-like macrophage-associated WGCNA module that the DepMap portal demonstrated was necessary for melanoma growth. Overexpressing VARS1 in vitro increased melanoma cell migration and invasion, while downregulating VARS1 had the opposite result. VARS1 overexpression promoted M2 macrophage polarization and increased TGF-β1 concentrations in tumor cell supernatant in vitro. VARS1 expression was inversely correlated with immune-related signaling pathways and the expression of several immune checkpoint genes. In addition, the VARS1 expression level helped predict the response to anti-PD-1 immunotherapy. Pan-cancer analysis demonstrated that VARS1 expression negatively correlated with CD8 T cell infiltration and the immune response-related pathways in most cancers. CONCLUSION We established an M2-like TAM-related prognostic model for melanoma and explored the role of VARS1 in melanoma progression, M2 macrophage polarization, and the development of immunotherapy resistance.
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Affiliation(s)
- Zhengquan Wu
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Munich, 81377, Munich, Germany.,Walter Brendel Center for Experimental Medicine, University of Munich, 81377, Munich, Germany
| | - Ke Lei
- Department of Dermatology, The Second People's Hospital of Chengdu, 610021, Chengdu, People's Republic of China
| | - Huaizhi Li
- Department of Endocrinology, Shenzhen University General Hospital, Shenzhen University, 518055, Shenzhen, People's Republic of China
| | - Jiali He
- Shenzhen Healthcare Committee Office, 518020, Shenzhen, People's Republic of China
| | - Enxian Shi
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Munich, 81377, Munich, Germany.
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Hashimoto S, Hashimoto A, Muromoto R, Kitai Y, Oritani K, Matsuda T. Central Roles of STAT3-Mediated Signals in Onset and Development of Cancers: Tumorigenesis and Immunosurveillance. Cells 2022; 11:cells11162618. [PMID: 36010693 PMCID: PMC9406645 DOI: 10.3390/cells11162618] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/12/2022] [Accepted: 08/20/2022] [Indexed: 02/07/2023] Open
Abstract
Since the time of Rudolf Virchow in the 19th century, it has been well-known that cancer-associated inflammation contributes to tumor initiation and progression. However, it remains unclear whether a collapse of the balance between the antitumor immune response via the immunological surveillance system and protumor immunity due to cancer-related inflammation is responsible for cancer malignancy. The majority of inflammatory signals affect tumorigenesis by activating signal transducer and activation of transcription 3 (STAT3) and nuclear factor-κB. Persistent STAT3 activation in malignant cancer cells mediates extremely widespread functions, including cell growth, survival, angiogenesis, and invasion and contributes to an increase in inflammation-associated tumorigenesis. In addition, intracellular STAT3 activation in immune cells causes suppressive effects on antitumor immunity and leads to the differentiation and mobilization of immature myeloid-derived cells and tumor-associated macrophages. In many cancer types, STAT3 does not directly rely on its activation by oncogenic mutations but has important oncogenic and malignant transformation-associated functions in both cancer and stromal cells in the tumor microenvironment (TME). We have reported a series of studies aiming towards understanding the molecular mechanisms underlying the proliferation of various types of tumors involving signal-transducing adaptor protein-2 as an adaptor molecule that modulates STAT3 activity, and we recently found that AT-rich interactive domain-containing protein 5a functions as an mRNA stabilizer that orchestrates an immunosuppressive TME in malignant mesenchymal tumors. In this review, we summarize recent advances in our understanding of the functional role of STAT3 in tumor progression and introduce novel molecular mechanisms of cancer development and malignant transformation involving STAT3 activation that we have identified to date. Finally, we discuss potential therapeutic strategies for cancer that target the signaling pathway to augment STAT3 activity.
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Affiliation(s)
- Shigeru Hashimoto
- Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan
- Correspondence: (S.H.); (T.M.)
| | - Ari Hashimoto
- Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Ryuta Muromoto
- Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Yuichi Kitai
- Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Kenji Oritani
- Department of Hematology, International University of Health and Welfare, Narita 286-8686, Japan
| | - Tadashi Matsuda
- Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
- Correspondence: (S.H.); (T.M.)
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Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-β signaling in regulatory T cells. Cell Rep 2022; 39:110986. [PMID: 35732125 DOI: 10.1016/j.celrep.2022.110986] [Citation(s) in RCA: 203] [Impact Index Per Article: 67.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 02/23/2022] [Accepted: 05/31/2022] [Indexed: 11/23/2022] Open
Abstract
Regulatory T (Treg) cells play a vital role in maintaining the immunosuppressive tumor microenvironment. Lactate is a crucial metabolite in cancer and is related to tumor prognosis, metastasis, and overall survival. In this study, we focus on the effects of lactate on Treg cells. In vitro, lactate improves Treg cell stability and function, whereas lactate degradation reduces Treg cell induction, increases antitumor immunity, and decreases tumor growth in mice. Mechanistically, lactate modulates Treg cell generation through lactylation of Lys72 in MOESIN, which improves MOESIN interaction with transforming growth factor β (TGF-β) receptor I and downstream SMAD3 signaling. Cotreatment with anti-PD-1 and a lactate dehydrogenase inhibitor has a stronger antitumor effect than anti-PD-1 alone. Individuals with hepatocellular carcinoma who responded to anti-PD-1 treatment have lower levels of MOESIN lactylation in Treg cells than nonresponding individuals. Thus, we identify lactate as an essential small molecule that reinforces Treg cells in the tumor microenvironment through lactylation.
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