|
1
|
Kim J, Li J, Wei J, Lim SA. Regulatory T Cell Metabolism: A Promising Therapeutic Target for Cancer Treatment? Immune Netw 2025; 25:e13. [PMID: 40078783 PMCID: PMC11896657 DOI: 10.4110/in.2025.25.e13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 02/09/2025] [Accepted: 02/11/2025] [Indexed: 03/14/2025] Open
Abstract
Regulatory T (Treg) cells are essential for maintaining immune homeostasis by suppressing excessive immune responses. In the context of cancer, however, Tregs promote immune evasion and tumor progression, particularly through their unique adaptations within the tumor microenvironment (TME). Recent research has emphasized how metabolic characteristics shape Treg activation, migration, and immunosuppressive function, revealing the impact of metabolic pathways on Treg fitness in homeostasis and within the TME. In this review, we first provide an overview of Tregs in cancer immunology, discussing their immunosuppressive roles and properties specific to the TME. We then examine the metabolic requirements for Treg activation and migration under normal conditions, followed by a discussion of how hypoxia, lactate accumulation, nutrient limitation, oxidative stress, and other TME-specific factors alter Treg metabolism and contribute to cancer immune evasion. Finally, we explore therapeutic strategies that target Treg metabolism within the TME, including pharmacological modulation of specific metabolic pathways to diminish Treg-mediated immunosuppression. Thus, we could suggest future directions and clinical implications for Treg-targeted metabolic modulation as a complementary approach in cancer treatment, setting the stage for novel strategies in immunotherapy.
Collapse
Affiliation(s)
- Jihyoun Kim
- Department of Life Science, Ewha Womans University, Seoul 03760, Korea
| | - Jiaoran Li
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Jun Wei
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Seon Ah Lim
- Department of Life Science, Ewha Womans University, Seoul 03760, Korea
- Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 03760, Korea
- Multitasking Macrophage Research Center, Ewha Womans University, Seoul 03760, Korea
| |
Collapse
|
|
2
|
Yan Y, Sun D, Hu J, Chen Y, Sun L, Yu H, Xiong Y, Huang Z, Xia H, Zhu X, Bian D, Sun F, Hou L, Wu C, Fan OR, Hu H, Zeng A, Zhang L, Sun YE, Wang C, Zhang P. Multi-omic profiling highlights factors associated with resistance to immuno-chemotherapy in non-small-cell lung cancer. Nat Genet 2025; 57:126-139. [PMID: 39658657 DOI: 10.1038/s41588-024-01998-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 10/18/2024] [Indexed: 12/12/2024]
Abstract
Although immune checkpoint blockade (ICB) therapies have shifted the treatment paradigm for non-small-cell lung cancer (NSCLC), many patients remain resistant. Here we characterize the tumor cell states and spatial cellular compositions of the NSCLC tumor microenvironment (TME) by analyzing single-cell transcriptomes of 232,080 cells and spatially resolved transcriptomes of tumors from 19 patients before and after ICB-chemotherapy. We find that tumor cells and secreted phosphoprotein 1-positive macrophages interact with collagen type XI alpha 1 chain-positive cancer-associated fibroblasts to stimulate the deposition and entanglement of collagen fibers at tumor boundaries, obstructing T cell infiltration and leading to poor prognosis. We also reveal distinct states of tertiary lymphoid structures (TLSs) in the TME. Activated TLSs are associated with improved prognosis, whereas a hypoxic microenvironment appears to suppress TLS development and is associated with poor prognosis. Our study provides novel insights into different cellular and molecular components corresponding to NSCLC ICB-chemotherapeutic responsiveness, which will benefit future individualized immuno-chemotherapy.
Collapse
Affiliation(s)
- Yilv Yan
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Dongqing Sun
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedics, Tongji Hospital, School of Life Science and Technology, Tongji University, Shanghai, China
- Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Junjie Hu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yue Chen
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Liangdong Sun
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Huansha Yu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yicheng Xiong
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Zhida Huang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Haoran Xia
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xinsheng Zhu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Dongliang Bian
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Fenghuan Sun
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Likun Hou
- Department of Pathology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Chunyan Wu
- Department of Pathology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Orion R Fan
- Stem Cell Translational Research Center, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Haiyang Hu
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - An Zeng
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
| | - Lele Zhang
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
| | - Yi Eve Sun
- Stem Cell Translational Research Center, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.
| | - Chenfei Wang
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedics, Tongji Hospital, School of Life Science and Technology, Tongji University, Shanghai, China.
- Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
- National Key Laboratory of Autonomous Intelligent Unmanned Systems, Tongji University, Shanghai, China.
- Frontier Science Center for Intelligent Autonomous Systems, Tongji University, Shanghai, China.
| | - Peng Zhang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
- Department of Thoracic Surgery, The First Affiliated Hospital of Shihezi University Medical College, Shihezi, China.
| |
Collapse
|
|
3
|
Rab SO, Roopashree R, Altalbawy FMA, Kumar MR, Chahar M, Singh M, Kubaev A, Alamir HTA, Mohammed F, Kadhim AJ, Alhadrawi M. Phytochemicals and Their Nanoformulations for Targeting Hepatocellular Carcinoma: Exploring Potential and Targeting Strategies. Cell Biochem Funct 2024; 42:e70013. [PMID: 39521962 DOI: 10.1002/cbf.70013] [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: 08/23/2024] [Revised: 10/18/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024]
Abstract
Hepatocellular carcinoma (HCC) continues to pose a global health concern, necessitating the exploration of innovative therapeutic approaches. In the recent decade, targeting tumor stroma consisting of extracellular matrix (ECM), immune cells, vascular system, hypoxia, and also suppressive mechanisms in HCC has attracted interest in repressing tumor growth and metastasis. Phytochemicals have attained considerable attention because of their manifold biological effects and high capacity for anticancer activities. These chemical agents have shown the capability to modulate different cells and secretions within the stroma of malignancies. In recent years, the development of nanoformulations has further enhanced the therapeutic potential of phytochemicals by improving their solubility, bioavailability, and targeted delivery to tumor tissues. This review aims to provide an encyclopedic overview of the potential of phytochemicals and their nanoformulations as promising therapeutic strategies for targeting HCC. The review initially highlights the broad array of phytochemicals exhibiting potent anticancer properties, including flavonoids, alkaloids, terpenoids, and phenolic compounds, among others. Then, the nanoformulations and modification of these agents will be reviewed. Finally, we will review the latest experiments that have examined the modulation of HCC using adjuvant phytochemicals and their nanoformulations.
Collapse
Affiliation(s)
- Safia Obaidur Rab
- Central Labs, King Khalid University, AlQura'a, Abha, Saudi Arabia
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - R Roopashree
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Farag M A Altalbawy
- Department of Chemistry, University College of Duba, University of Tabuk, Tabuk, Saudi Arabia
| | - M Ravi Kumar
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, India
| | - Mamata Chahar
- Department of Chemistry, NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, Rajasthan, India
| | - Manmeet Singh
- Department of Applied Sciences, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab, India
| | - Aziz Kubaev
- Department of Maxillofacial Surgery, Samarkand State Medical University, Samarkand, Uzbekistan
| | | | - Faraj Mohammed
- Department of Pharmacy, Al-Manara College for Medical Sciences, Amarah, Maysan, Iraq
| | - Abed J Kadhim
- Department of Medical Engineering, Al-Nisour University College, Baghdad, Iraq
| | - Merwa Alhadrawi
- College of Technical Engineering, The Islamic University, Najaf, Iraq
- College of Technical Engineering, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Technical Engineering, The Islamic University of Babylon, Babylon, Iraq
| |
Collapse
|
|
4
|
Ogunlusi O, Sarkar M, Chakrabarti A, Boland DJ, Nguyen T, Sampson J, Nguyen C, Fails D, Jones-Hall Y, Fu L, Mallick B, Keene A, Jones J, Sarkar TR. Disruption of Circadian Clock Induces Abnormal Mammary Morphology and Aggressive Basal Tumorigenesis by Enhancing LILRB4 Signaling. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.19.585534. [PMID: 38562905 PMCID: PMC10983926 DOI: 10.1101/2024.03.19.585534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Epidemiological studies have shown that circadian rhythm disruption (CRD) is associated with the risk of breast cancer. However, the role of CRD in mammary gland morphology and aggressive basal mammary tumorigenesis and the molecular mechanisms underlying CRD and cancer risk remain unknown. To investigate the effect of CRD on aggressive tumorigenesis, a genetically engineered mouse model that recapitulates the human basal type of breast cancer was used for this study. The effect of CRD on mammary gland morphology was investigated using wild-type mice model. The impact of CRD on the tumor microenvironment was investigated using the tumors from LD12:12 and CRD mice via scRNA seq. ScRNA seq was substantiated by multiplexing immunostaining, flow cytometry, and realtime PCR. The effect of LILRB4 immunotherapy on CRD-induced tumorigenesis was also investigated. Here we identified the impact of CRD on basal tumorigenesis and mammary gland morphology and identified the role of LILRB4 on CRD-induced lung metastasis. We found that chronic CRD disrupted mouse mammary gland morphology and increased tumor burden, and lung metastasis and induced an immunosuppressive tumor microenvironment by enhancing LILRB4a expression. Moreover, CRD increased the M2-macrophage and regulatory T-cell populations but decreased the M1-macrophage, and dendritic cell populations. Furthermore, targeted immunotherapy against LILRB4 reduced CRD-induced immunosuppressive microenvironment and lung metastasis. These findings identify and implicate LILRB4a as a link between CRD and aggressive mammary tumorigenesis. This study also establishes the potential role of the targeted LILRB4a immunotherapy as an inhibitor of CRD-induced lung metastasis.
Collapse
|
|
5
|
Liu Y, Chen X, Zhang X, Guo J, Tang Y, Jin C, Wu M. CCL28 promotes progression of hepatocellular carcinoma through PDGFD-regulated MMP9 and VEGFA pathways. Discov Oncol 2024; 15:324. [PMID: 39085670 PMCID: PMC11291847 DOI: 10.1007/s12672-024-01185-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 07/22/2024] [Indexed: 08/02/2024] Open
Abstract
Hepatocellular carcinoma (HCC) remains a major global health concern with limited therapeutic options and poor prognosis. Chemokines have emerged as critical regulators in the progression and metastasis of HCC. This study aims to investigate the mechanisms involved in CCL28-promoted progression of HCC and provide novel therapeutic targets for HCC treatment. Relationship between CCL28 expression and HCC progression were investigated by bioinformatic analysis and immunohistochemical staining assays. CCK-8, Transwell, and colony formation assay were conducted to explore the impact of CCL28 on the growth, migration and invasion of HCC cells. Quantitative real-time PCR and western blotting assays were performed to learn potential molecular mechanisms underlying the transformation of HCC driven by CCL28. The results showed that there was a direct link between increased CCL28 levels and the advancement of HCC, leading to a worse outcome. CCL28 significantly augmented malignant transformation of HCC cells, containing proliferation, migration, invasion, and clonogenicity, via activation of PDGFD-regulated MMP9 and VEGFA pathways. CCL28 emerges as a pivotal contributor to HCC tumorigenesis, propelling HCC development through the PDGFD signaling pathway. Our findings unveil potential therapeutic targets for HCC treatment.
Collapse
Affiliation(s)
- Youyi Liu
- Wuxi School of Medicine, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, 214122, Jiangsu, China
| | - Xingyi Chen
- Wuxi School of Medicine, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, 214122, Jiangsu, China
| | - Xiading Zhang
- Wuxi Higher Health Vocational Technology School, Wuxi, 214000, China
| | - Jingrou Guo
- Wuxi School of Medicine, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, 214122, Jiangsu, China
| | - Yifei Tang
- Wuxi School of Medicine, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, 214122, Jiangsu, China
| | - Cheng Jin
- Department of Hepatobiliary Surgery, Affiliated Hospital of Jiangnan University, Jiangnan University, No. 1000 Hefeng Road, Wuxi, 214041, Jiangsu, China.
| | - Minchen Wu
- Wuxi School of Medicine, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, 214122, Jiangsu, China.
| |
Collapse
|
|
6
|
Muckenhuber M, Mengrelis K, Weijler AM, Steiner R, Kainz V, Buresch M, Regele H, Derdak S, Kubetz A, Wekerle T. IL-6 inhibition prevents costimulation blockade-resistant allograft rejection in T cell-depleted recipients by promoting intragraft immune regulation in mice. Nat Commun 2024; 15:4309. [PMID: 38830846 PMCID: PMC11148062 DOI: 10.1038/s41467-024-48574-w] [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: 08/28/2023] [Accepted: 04/30/2024] [Indexed: 06/05/2024] Open
Abstract
The efficacy of costimulation blockade with CTLA4-Ig (belatacept) in transplantation is limited due to T cell-mediated rejection, which also persists after induction with anti-thymocyte globulin (ATG). Here, we investigate why ATG fails to prevent costimulation blockade-resistant rejection and how this barrier can be overcome. ATG did not prevent graft rejection in a murine heart transplant model of CTLA4-Ig therapy and induced a pro-inflammatory cytokine environment. While ATG improved the balance between regulatory T cells (Treg) and effector T cells in the spleen, it had no such effect within cardiac allografts. Neutralizing IL-6 alleviated graft inflammation, increased intragraft Treg frequencies, and enhanced intragraft IL-10 and Th2-cytokine expression. IL-6 blockade together with ATG allowed CTLA4-Ig therapy to achieve long-term, rejection-free heart allograft survival. This beneficial effect was abolished upon Treg depletion. Combining ATG with IL-6 blockade prevents costimulation blockade-resistant rejection, thereby eliminating a major impediment to clinical use of costimulation blockers in transplantation.
Collapse
Affiliation(s)
- Moritz Muckenhuber
- Div. of Transplantation, Dept. of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Konstantinos Mengrelis
- Div. of Transplantation, Dept. of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Anna Marianne Weijler
- Div. of Transplantation, Dept. of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Romy Steiner
- Div. of Transplantation, Dept. of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Verena Kainz
- Div. of Transplantation, Dept. of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Marlena Buresch
- Div. of Transplantation, Dept. of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Heinz Regele
- Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
| | - Sophia Derdak
- Core Facilities, Medical University of Vienna, Vienna, Austria
| | - Anna Kubetz
- Div. of Transplantation, Dept. of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Thomas Wekerle
- Div. of Transplantation, Dept. of General Surgery, Medical University of Vienna, Vienna, Austria.
| |
Collapse
|
|
7
|
Ma Y, Lv H, Xing F, Xiang W, Wu Z, Feng Q, Wang H, Yang W. Cancer stem cell-immune cell crosstalk in the tumor microenvironment for liver cancer progression. Front Med 2024; 18:430-445. [PMID: 38600350 DOI: 10.1007/s11684-023-1049-z] [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: 06/09/2023] [Accepted: 11/15/2023] [Indexed: 04/12/2024]
Abstract
Crosstalk between cancer cells and the immune microenvironment is determinant for liver cancer progression. A tumor subpopulation called liver cancer stem cells (CSCs) significantly accounts for the initiation, metastasis, therapeutic resistance, and recurrence of liver cancer. Emerging evidence demonstrates that the interaction between liver CSCs and immune cells plays a crucial role in shaping an immunosuppressive microenvironment and determining immunotherapy responses. This review sheds light on the bidirectional crosstalk between liver CSCs and immune cells for liver cancer progression, as well as the underlying molecular mechanisms after presenting an overview of liver CSCs characteristic and their microenvironment. Finally, we discuss the potential application of liver CSCs-targeted immunotherapy for liver cancer treatment.
Collapse
Affiliation(s)
- Yue Ma
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Hongwei Lv
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China
| | - Fuxue Xing
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Wei Xiang
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Zixin Wu
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Qiyu Feng
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Hongyang Wang
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China.
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China.
- Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai, 200438, China.
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, 200438, China.
| | - Wen Yang
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China.
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China.
- Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai, 200438, China.
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, 200438, China.
| |
Collapse
|
|
8
|
Blériot C, Dunsmore G, Alonso-Curbelo D, Ginhoux F. A temporal perspective for tumor-associated macrophage identities and functions. Cancer Cell 2024; 42:747-758. [PMID: 38670090 DOI: 10.1016/j.ccell.2024.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 02/13/2024] [Accepted: 04/04/2024] [Indexed: 04/28/2024]
Abstract
Cancer is a progressive disease that can develop and evolve over decades, with inflammation playing a central role at each of its stages, from tumor initiation to metastasis. In this context, macrophages represent well-established bridges reciprocally linking inflammation and cancer via an array of diverse functions that have spurred efforts to classify them into subtypes. Here, we discuss the intertwines between macrophages, inflammation, and cancer with an emphasis on temporal dynamics of macrophage diversity and functions in pre-malignancy and cancer. By instilling temporal dynamism into the more static classic view of tumor-associated macrophage biology, we propose a new framework to better contextualize their significance in the inflammatory processes that precede and result from the onset of cancer and shape its evolution.
Collapse
Affiliation(s)
- Camille Blériot
- Gustave Roussy, INSERM, Villejuif, France; Institut Necker des Enfants Malades (INEM), INSERM, CNRS, Université Paris Cité, Paris, France
| | | | - Direna Alonso-Curbelo
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
| | - Florent Ginhoux
- Gustave Roussy, INSERM, Villejuif, France; Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai, China; Translational Immunology Institute, SingHealth Duke-NUS, Singapore, Singapore.
| |
Collapse
|
|
9
|
Wu Z, Sun L, Xu Y, Huang H, Wu Z, Qiu B, Yan J, Yin X. The Value of Chemokine and Chemokine Receptors in Diagnosis, Prognosis, and Immunotherapy of Hepatocellular Carcinoma. Cancer Manag Res 2024; 16:403-420. [PMID: 38736589 PMCID: PMC11086648 DOI: 10.2147/cmar.s450959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 04/20/2024] [Indexed: 05/14/2024] Open
Abstract
Background Chemokines and chemokine receptors (CCRs) are involved in a variety of anti-tumour and pro-tumour immune processes in vivo, such as angiogenesis, metastasis, proliferation and invasiveness, and influence patient prognosis and response to therapy. Methods CCRs differentially expressed in HCC and associated with prognosis were extracted from TCGA and GEO databases, and the obtained CCRs were then used to construct signature genes, and the signature gene were selected for expression validation as well as functional experiments to explore the role of CCRs in the treatment and prognosis of HCC. Results We constructed a prognostic model including five CCRs (CCL20, CCL23, CCR3, CCR10, and CXCR3) and validated the expression of signature genes. The model's risk score is an independent prognostic factor for HCC. We have also developed prognostic model nomograms for clinical use. In addition, we validated that CCR3 expression is associated with poor prognosis in HCC, and the proliferation and migration ability of HCC cells was significantly inhibited after interfering with the expression of CCR3 in MHCC-LM3. We also looked at differences in pathway enrichment, immune infiltration and immune checkpoints. Finally, we found that risk scores were also correlated with drug sensitivity, the high-risk group had a better sensitivity to sorafenib. Conclusion The CCRs-related gene signature may better assess HCC prognosis and response to immunotherapy and tyrosine kinase inhibitors such as sorafenib in HCC, providing prospective solutions for diagnosis and treatment.
Collapse
Affiliation(s)
- Zhengyi Wu
- Hepatobiliary Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China
| | - Liang Sun
- Hepatobiliary Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China
| | - Yongkang Xu
- Hepatobiliary Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China
| | - He Huang
- Hepatobiliary Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China
| | - Zhipeng Wu
- Hepatobiliary Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China
| | - Bingbing Qiu
- Hepatobiliary Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China
| | - Jinlong Yan
- Hepatobiliary Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China
| | - Xiangbao Yin
- Hepatobiliary Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China
| |
Collapse
|
|
10
|
Qian J, Huang C, Wang M, Liu Y, Zhao Y, Li M, Zhang X, Gao X, Zhang Y, Wang Y, Huang J, Li J, Zhou Q, Liu R, Wang X, Cui J, Yang Y. Nuclear translocation of metabolic enzyme PKM2 participates in high glucose-promoted HCC metastasis by strengthening immunosuppressive environment. Redox Biol 2024; 71:103103. [PMID: 38471282 PMCID: PMC10945175 DOI: 10.1016/j.redox.2024.103103] [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: 01/18/2024] [Revised: 02/14/2024] [Accepted: 02/23/2024] [Indexed: 03/14/2024] Open
Abstract
Although some cohort studies have indicated a close association between diabetes and HCC, the underlying mechanism about the contribution of diabetes to HCC progression remains largely unknown. In the study, we applied a novel HCC model in SD rat with diabetes and a series of high glucose-stimulated cell experiments to explore the effect of a high glucose environment on HCC metastasis and its relevant mechanism. Our results uncovered a novel regulatory mechanism by which nuclear translocation of metabolic enzyme PKM2 mediated high glucose-promoted HCC metastasis. Specifically, high glucose-increased PKM2 nuclear translocation downregulates chemerin expression through the redox protein TRX1, and then strengthens immunosuppressive environment to promote HCC metastasis. To the best of our knowledge, this is the first report to elucidate the great contribution of a high glucose environment to HCC metastasis from a new perspective of enhancing the immunosuppressive microenvironment. Simultaneously, this work also highlights a previously unidentified non-metabolic role of PKM2 and opens a novel avenue for cross research and intervention for individuals with HCC and comorbid diabetes.
Collapse
Affiliation(s)
- Jiali Qian
- Department of endocrinology, Huashan Hospital, Fudan University, Shanghai, China
| | - Chuxin Huang
- Department of endocrinology, Huashan Hospital, Fudan University, Shanghai, China
| | - Mimi Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Ying Liu
- Department of endocrinology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yingying Zhao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Miao Li
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Xi Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Xiangyu Gao
- Department of endocrinology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yawen Zhang
- Department of endocrinology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yi Wang
- Department of endocrinology, Huashan Hospital, Fudan University, Shanghai, China
| | - Jinya Huang
- Department of endocrinology, Huashan Hospital, Fudan University, Shanghai, China
| | - Jiajun Li
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Qiwen Zhou
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Rui Liu
- Department of endocrinology, Huashan Hospital, Fudan University, Shanghai, China
| | - Xuanchun Wang
- Department of endocrinology, Huashan Hospital, Fudan University, Shanghai, China
| | - Jiefeng Cui
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
| | - Yehong Yang
- Department of endocrinology, Huashan Hospital, Fudan University, Shanghai, China.
| |
Collapse
|
|
11
|
Zhang Y, Guo F, Wang Y. Hypoxic tumor microenvironment: Destroyer of natural killer cell function. Chin J Cancer Res 2024; 36:138-150. [PMID: 38751439 PMCID: PMC11090795 DOI: 10.21147/j.issn.1000-9604.2024.02.04] [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: 01/19/2024] [Accepted: 04/10/2024] [Indexed: 05/18/2024] Open
Abstract
In recent years, immunotherapy has made remarkable progress in treating certain tumors and hematological malignancies. However, the efficacy of natural killer (NK) cells, which are an important subset of innate lymphocytes used in anticancer immunotherapy, remains limited. Hypoxia, a critical characteristic of the tumor microenvironment (TME), is involved in tumor development and resistance to radiotherapy, chemotherapy, and immunotherapy. Moreover, hypoxia contributes to the impairment of NK cell function and may be a significant factor that limits their therapeutic effects. Targeted hypoxia therapy has emerged as a promising research area for enhancing the efficacy of NK cell therapy. Therefore, understanding how the hypoxic TME influences NK cell function is crucial for improving antitumor treatment outcomes.
Collapse
Affiliation(s)
- Yongfei Zhang
- Cancer Center, the First Hospital of Jilin University, Changchun 130021, China
| | - Feifei Guo
- Cancer Center, the First Hospital of Jilin University, Changchun 130021, China
| | - Yufeng Wang
- Cancer Center, the First Hospital of Jilin University, Changchun 130021, China
| |
Collapse
|
|
12
|
Yoo W, Kim AK, Kook HU, Noh K. Comprehensive analysis on clinical significance and therapeutic targets of LDL receptor related protein 11 (LRP11) in liver hepatocellular carcinoma. Front Pharmacol 2024; 15:1338929. [PMID: 38425648 PMCID: PMC10902445 DOI: 10.3389/fphar.2024.1338929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 01/31/2024] [Indexed: 03/02/2024] Open
Abstract
LDL lipoprotein receptor-related protein 11 (LRP11) plays a role in several tumors. However, their roles in hepatocellular carcinoma remain unclear. The present study aimed to explore the expression profile and prognostic value of LRP11 in liver hepatocellular carcinoma (LIHC) patients using various cancer databases and bioinformatic tools. In bioinformatics analysis, The Cancer Genome Atlas datasets showed increased LRP11 expression in tumor tissues compared to that in non-tumor tissues in various cancers. Moreover, patients with high expression LRP11 correlated with poor prognosis and clinical features. The LRP11 expression positively correlated with the infiltration of immune cells such as macrophages, neutrophils, and myeloid-derived suppressor cells and a combination of high LRP11 expression and high immune infiltrates was associated with the worst survival in LIHC tumors. Our results also indicated that LRP11 expression was closely associated with immune-modulate function, such as antigen presentation. In DNA methylation profiling, hypomethylation of LRP11 is widely observed in tumors and has prognostic value in LIHC patients. Functional enrichment analysis revealed that LIHC-specific LRP11 interacting genes are involved in protein binding, intracellular processing, and G-protein-related signaling pathways. Analyses of drug sensitivity and immune checkpoint inhibitor predict a number of drugs that could potentially be used to target LRP11. In addition, in vitro experiments verified the promoting effect of LRP11 on the migration, invasion, and colony formation capacity of hepatocellular carcinoma cells. Collectively, our results aided a better understanding of the clinical significance of LRP11 in gene expression, functional interactions, and epigenetic regulation in LIHC and suggested that it may be a useful prognostic biomarker for LIHC patients.
Collapse
Affiliation(s)
- Wonbeak Yoo
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Ae-Kyeong Kim
- Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Hae Un Kook
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Kyunghee Noh
- Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Nanobiotechnology, University of Science and Technology (UST), Daejeon, Republic of Korea
| |
Collapse
|
|
13
|
Wang X, Yuan Z, Li Z, He X, Zhang Y, Wang X, Su J, Wu X, Li M, Du F, Chen Y, Deng S, Zhao Y, Shen J, Yi T, Xiao Z. Key oncogenic signaling pathways affecting tumor-infiltrating lymphocytes infiltration in hepatocellular carcinoma: basic principles and recent advances. Front Immunol 2024; 15:1354313. [PMID: 38426090 PMCID: PMC10902128 DOI: 10.3389/fimmu.2024.1354313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 01/29/2024] [Indexed: 03/02/2024] Open
Abstract
The incidence of hepatocellular carcinoma (HCC) ranks first among primary liver cancers, and its mortality rate exhibits a consistent annual increase. The treatment of HCC has witnessed a significant surge in recent years, with the emergence of targeted immune therapy as an adjunct to early surgical resection. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has shown promising results in other types of solid tumors. This article aims to provide a comprehensive overview of the intricate interactions between different types of TILs and their impact on HCC, elucidate strategies for targeting neoantigens through TILs, and address the challenges encountered in TIL therapies along with potential solutions. Furthermore, this article specifically examines the impact of oncogenic signaling pathways activation within the HCC tumor microenvironment on the infiltration dynamics of TILs. Additionally, a concise overview is provided regarding TIL preparation techniques and an update on clinical trials investigating TIL-based immunotherapy in solid tumors.
Collapse
Affiliation(s)
- Xiang Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Zijun Yuan
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Zhengbo Li
- Department of Laboratory Medicine, The Longmatan District People’s Hospital, Luzhou, China
| | - Xinyu He
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Yinping Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xingyue Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Jiahong Su
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Shuai Deng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Tao Yi
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| |
Collapse
|
|
14
|
Kondo M, Kumagai S, Nishikawa H. Metabolic advantages of regulatory T cells dictated by cancer cells. Int Immunol 2024; 36:75-86. [PMID: 37837615 DOI: 10.1093/intimm/dxad035] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 10/13/2023] [Indexed: 10/16/2023] Open
Abstract
Cancer cells employ glycolysis for their survival and growth (the "Warburg effect"). Consequently, surrounding cells including immune cells in the tumor microenvironment (TME) are exposed to hypoglycemic, hypoxic, and low pH circumstances. Since effector T cells depend on the glycolysis for their survival and functions, the metabolically harsh TME established by cancer cells is unfavorable, resulting in the impairment of effective antitumor immune responses. By contrast, immunosuppressive cells such as regulatory T (Treg) cells can infiltrate, proliferate, survive, and exert immunosuppressive functions in the metabolically harsh TME, indicating the different metabolic dependance between effector T cells and Treg cells. Indeed, some metabolites that are harmful for effector T cells can be utilized by Treg cells; lactic acid, a harmful metabolite for effector T cells, is available for Treg cell proliferation and functions. Deficiency of amino acids such as tryptophan and glutamine in the TME impairs effector T cell activation but increases Treg cell populations. Furthermore, hypoxia upregulates fatty acid oxidation via hypoxia-inducible factor 1α (HIF-1α) and promotes Treg cell migration. Adenosine is induced by the ectonucleotidases CD39 and CD73, which are strongly induced by HIF-1α, and reportedly accelerates Treg cell development by upregulating Foxp3 expression in T cells via A2AR-mediated signals. Therefore, this review focuses on the current views of the unique metabolism of Treg cells dictated by cancer cells. In addition, potential cancer combination therapies with immunotherapy and metabolic molecularly targeted reagents that modulate Treg cells in the TME are discussed to develop "immune metabolism-based precision medicine".
Collapse
Affiliation(s)
- Masaki Kondo
- Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo 104-0045, Japan
- Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Chiba 277-8577, Japan
- Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Shogo Kumagai
- Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo 104-0045, Japan
- Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Chiba 277-8577, Japan
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Hiroyoshi Nishikawa
- Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo 104-0045, Japan
- Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Chiba 277-8577, Japan
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| |
Collapse
|
|
15
|
Wang Y, Sun Y, Li X, Yu X, Zhang K, Liu J, Tian Q, Zhang H, Du X, Wang S. Progress in the treatment of malignant ascites. Crit Rev Oncol Hematol 2024; 194:104237. [PMID: 38128628 DOI: 10.1016/j.critrevonc.2023.104237] [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: 06/05/2023] [Revised: 11/14/2023] [Accepted: 12/14/2023] [Indexed: 12/23/2023] Open
Abstract
Malignant ascites occurs as a symptom of the terminal stage of cancer, affecting the quality of life through abdominal distension, pain, nausea, anorexia, dyspnea and other symptoms. We describe the current main drug treatments in addition to surgery according to the traditional and new strategies. Traditional treatments were based on anti-tumor chemotherapy and traditional Chinese medicine treatments, as well as diuretics to relieve the patient's symptoms. New treatments mainly involve photothermal therapy, intestinal therapy and targeted immunity. This study emphasizes that both traditional and new therapies have certain advantages and disadvantages, and medication should be adjusted according to different periods of use and different patients. In conclusion, this article reviews the literature to systematically describe the primary treatment modalities for malignant ascites.
Collapse
Affiliation(s)
- Yiqiu Wang
- Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou, Zhejiang 311121, China; School of Pharmacy, Hangzhou Normal University, Hangzhou, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Yunting Sun
- Hangzhou TCM Hospital Afflitiated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang 311121, China.
| | - Xinyue Li
- Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou, Zhejiang 311121, China; School of Pharmacy, Hangzhou Normal University, Hangzhou, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Xiaoli Yu
- Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou, Zhejiang 311121, China; School of Pharmacy, Hangzhou Normal University, Hangzhou, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Keying Zhang
- Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou, Zhejiang 311121, China; School of Pharmacy, Hangzhou Normal University, Hangzhou, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Jinglei Liu
- Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou, Zhejiang 311121, China; School of Pharmacy, Hangzhou Normal University, Hangzhou, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Qingchang Tian
- Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou, Zhejiang 311121, China; School of Pharmacy, Hangzhou Normal University, Hangzhou, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Honghua Zhang
- Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou, Zhejiang 311121, China; School of Pharmacy, Hangzhou Normal University, Hangzhou, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Xiao Du
- Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou, Zhejiang 311121, China; School of Pharmacy, Hangzhou Normal University, Hangzhou, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
| | - Shuling Wang
- Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou, Zhejiang 311121, China; School of Pharmacy, Hangzhou Normal University, Hangzhou, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
| |
Collapse
|
|
16
|
Bigos KJA, Quiles CG, Lunj S, Smith DJ, Krause M, Troost EGC, West CM, Hoskin P, Choudhury A. Tumour response to hypoxia: understanding the hypoxic tumour microenvironment to improve treatment outcome in solid tumours. Front Oncol 2024; 14:1331355. [PMID: 38352889 PMCID: PMC10861654 DOI: 10.3389/fonc.2024.1331355] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 01/08/2024] [Indexed: 02/16/2024] Open
Abstract
Hypoxia is a common feature of solid tumours affecting their biology and response to therapy. One of the main transcription factors activated by hypoxia is hypoxia-inducible factor (HIF), which regulates the expression of genes involved in various aspects of tumourigenesis including proliferative capacity, angiogenesis, immune evasion, metabolic reprogramming, extracellular matrix (ECM) remodelling, and cell migration. This can negatively impact patient outcomes by inducing therapeutic resistance. The importance of hypoxia is clearly demonstrated by continued research into finding clinically relevant hypoxia biomarkers, and hypoxia-targeting therapies. One of the problems is the lack of clinically applicable methods of hypoxia detection, and lack of standardisation. Additionally, a lot of the methods of detecting hypoxia do not take into consideration the complexity of the hypoxic tumour microenvironment (TME). Therefore, this needs further elucidation as approximately 50% of solid tumours are hypoxic. The ECM is important component of the hypoxic TME, and is developed by both cancer associated fibroblasts (CAFs) and tumour cells. However, it is important to distinguish the different roles to develop both biomarkers and novel compounds. Fibronectin (FN), collagen (COL) and hyaluronic acid (HA) are important components of the ECM that create ECM fibres. These fibres are crosslinked by specific enzymes including lysyl oxidase (LOX) which regulates the stiffness of tumours and induces fibrosis. This is partially regulated by HIFs. The review highlights the importance of understanding the role of matrix stiffness in different solid tumours as current data shows contradictory results on the impact on therapeutic resistance. The review also indicates that further research is needed into identifying different CAF subtypes and their exact roles; with some showing pro-tumorigenic capacity and others having anti-tumorigenic roles. This has made it difficult to fully elucidate the role of CAFs within the TME. However, it is clear that this is an important area of research that requires unravelling as current strategies to target CAFs have resulted in worsened prognosis. The role of immune cells within the tumour microenvironment is also discussed as hypoxia has been associated with modulating immune cells to create an anti-tumorigenic environment. Which has led to the development of immunotherapies including PD-L1. These hypoxia-induced changes can confer resistance to conventional therapies, such as chemotherapy, radiotherapy, and immunotherapy. This review summarizes the current knowledge on the impact of hypoxia on the TME and its implications for therapy resistance. It also discusses the potential of hypoxia biomarkers as prognostic and predictive indictors of treatment response, as well as the challenges and opportunities of targeting hypoxia in clinical trials.
Collapse
Affiliation(s)
- Kamilla JA. Bigos
- Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
| | - Conrado G. Quiles
- Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
| | - Sapna Lunj
- Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
| | - Danielle J. Smith
- Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
| | - Mechthild Krause
- German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- OncoRay – National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany
- Translational Radiooncology and Clinical Radiotherapy, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany
- Translational Radiation Oncology, National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany
- Translational Radiooncology and Clinical Radiotherapy and Image-guided High Precision Radiotherapy, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Translational Radiooncology and Clinical Radiotherapy and Image-guided High Precision Radiotherapy, Helmholtz Association / Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
- School of Medicine, Technische Universitat Dresden, Dresden, Germany
| | - Esther GC. Troost
- OncoRay – National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany
- Translational Radiation Oncology, National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany
- Translational Radiooncology and Clinical Radiotherapy and Image-guided High Precision Radiotherapy, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Translational Radiooncology and Clinical Radiotherapy and Image-guided High Precision Radiotherapy, Helmholtz Association / Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
- School of Medicine, Technische Universitat Dresden, Dresden, Germany
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Institute of Radiooncology – OncoRay, Helmholtz-Zentrum Dresden-Rossendorf, Rossendorf, Germany
| | - Catharine M. West
- Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester, United Kingdom
| | - Peter Hoskin
- Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
- Mount Vernon Cancer Centre, Northwood, United Kingdom
| | - Ananya Choudhury
- Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
- Christie Hospital NHS Foundation Trust, Manchester, Germany
| |
Collapse
|
|
17
|
Liu J, Jiang Y, Chen L, Qian Z, Zhang Y. Associations between HIFs and tumor immune checkpoints: mechanism and therapy. Discov Oncol 2024; 15:2. [PMID: 38165484 PMCID: PMC10761656 DOI: 10.1007/s12672-023-00836-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 11/21/2023] [Indexed: 01/03/2024] Open
Abstract
Hypoxia, which activates a variety of signaling pathways to enhance tumor cell growth and metabolism, is among the primary features of tumor cells. Hypoxia-inducible factors (HIFs) have a substantial impact on a variety of facets of tumor biology, such as epithelial-mesenchymal transition, metabolic reprogramming, angiogenesis, and improved radiation resistance. HIFs induce hypoxia-adaptive responses in tumor cells. Many academics have presented preclinical and clinical research targeting HIFs in tumor therapy, highlighting the potential applicability of targeted HIFs. In recent years, the discovery of numerous pharmacological drugs targeting the regulatory mechanisms of HIFs has garnered substantial attention. Additionally, HIF inhibitors have attained positive results when used in conjunction with traditional oncology radiation and/or chemotherapy, as well as with the very promising addition of tumor immunotherapy. Immune checkpoint inhibitors (CPIs), which are employed in a range of cancer treatments over the past decades, are essential in tumor immunotherapy. Nevertheless, the use of immunotherapy has been severely hampered by tumor resistance and treatment-related toxicity. According to research, HIF inhibitors paired with CPIs may be game changers for multiple malignancies, decreasing malignant cell plasticity and cancer therapy resistance, among other things, and opening up substantial new pathways for immunotherapy drug development. The structure, activation mechanisms, and pharmacological sites of action of the HIF family are briefly reviewed in this work. This review further explores the interactions between HIF inhibitors and other tumor immunotherapy components and covers the potential clinical use of HIF inhibitors in combination with CPIs.
Collapse
Affiliation(s)
- Jiayu Liu
- Department of Oncology, Wuxi Maternal and Child Health Hospital, Wuxi School of Medicine, Jiangnan University, Wuxi, 214002, Jiangsu, China
| | - Ying Jiang
- Department of Oncology, Wuxi Maternal and Child Health Hospital, Wuxi School of Medicine, Jiangnan University, Wuxi, 214002, Jiangsu, China
| | - Lingyan Chen
- Wuxi Maternal and Child Health Hospital, Nanjing Medical University, Nanjing, 214000, Jiangsu, China
| | - Zhiwen Qian
- Wuxi Maternal and Child Health Hospital, Nanjing Medical University, Nanjing, 214000, Jiangsu, China
| | - Yan Zhang
- Department of Oncology, Wuxi Maternal and Child Health Hospital, Wuxi School of Medicine, Jiangnan University, Wuxi, 214002, Jiangsu, China.
- Wuxi Maternal and Child Health Hospital, Nanjing Medical University, Nanjing, 214000, Jiangsu, China.
| |
Collapse
|
|
18
|
Frąszczak K, Barczyński B. The Role of Cancer Stem Cell Markers in Ovarian Cancer. Cancers (Basel) 2023; 16:40. [PMID: 38201468 PMCID: PMC10778113 DOI: 10.3390/cancers16010040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 12/15/2023] [Accepted: 12/17/2023] [Indexed: 01/12/2024] Open
Abstract
Ovarian cancer is the most lethal gynaecological cancer and the eighth most common female cancer. The early diagnosis of ovarian cancer remains a clinical problem despite the significant development of technology. Nearly 70% of patients with ovarian cancer are diagnosed with stages III-IV metastatic disease. Reliable diagnostic and prognostic biomarkers are currently lacking. Ovarian cancer recurrence and resistance to chemotherapy pose vital problems and translate into poor outcomes. Cancer stem cells appear to be responsible for tumour recurrence resulting from chemotherapeutic resistance. These cells are also crucial for tumour initiation due to the ability to self-renew, differentiate, avoid immune destruction, and promote inflammation and angiogenesis. Studies have confirmed an association between CSC occurrence and resistance to chemotherapy, subsequent metastases, and cancer relapses. Therefore, the elimination of CSCs appears important for overcoming drug resistance and improving prognoses. This review focuses on the expression of selected ovarian CSC markers, including CD133, CD44, CD24, CD117, and aldehyde dehydrogenase 1, which show potential prognostic significance. Some markers expressed on the surface of CSCs correlate with clinical features and can be used for the diagnosis and prognosis of ovarian cancer. However, due to the heterogeneity and plasticity of CSCs, the determination of specific CSC phenotypes is difficult.
Collapse
Affiliation(s)
| | - Bartłomiej Barczyński
- 1st Chair and Department of Oncological Gynaecology and Gynaecology, Medical University in Lublin, 20-081 Lublin, Poland;
| |
Collapse
|
|
19
|
Chen Y, Zhou Y, Yan Z, Tong P, Xia Q, He K. Effect of infiltrating immune cells in tumor microenvironment on metastasis of hepatocellular carcinoma. Cell Oncol (Dordr) 2023; 46:1595-1604. [PMID: 37414962 DOI: 10.1007/s13402-023-00841-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/27/2023] [Indexed: 07/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent human malignancies, leading to poor prognosis due to its high recurrence and metastasis rates. In recent years it has become increasingly evident that the tumor microenvironment (TME) plays an important role in tumor progression and metastasis. Tumor microenvironment (TME) refers to the complex tissue environment of tumor occurrence and development. Here, we summarize the development of HCC and the role of cellular and non-cellular components of the TME in the metastasis HCC, with particular reference to tumor-infiltrating immune cells. We also discuss some of the possible therapeutic targets for the TME and the future prospectives of this evolving field. SIGNIFICANCE: This review provides a comprehensive analysis of the role of the infiltrating immune cells in TME in the metastasis of HCC and highlights the future outlook for targeted therapy of the TME in the context of recent experiments revealing a number of therapeutic targets targeting the TME.
Collapse
Affiliation(s)
- Yiwen Chen
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China
- Shanghai Institute of Transplantation, Shanghai, China
| | - Yuhang Zhou
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China
- Shanghai Institute of Transplantation, Shanghai, China
| | - Ziyang Yan
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China
- Shanghai Institute of Transplantation, Shanghai, China
| | - Peilin Tong
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China
- Shanghai Institute of Transplantation, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China.
- Shanghai Institute of Transplantation, Shanghai, China.
| | - Kang He
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China.
- Shanghai Institute of Transplantation, Shanghai, China.
| |
Collapse
|
|
20
|
Nayak V, Patra S, Singh KR, Ganguly B, Kumar DN, Panda D, Maurya GK, Singh J, Majhi S, Sharma R, Pandey SS, Singh RP, Kerry RG. Advancement in precision diagnosis and therapeutic for triple-negative breast cancer: Harnessing diagnostic potential of CRISPR-cas & engineered CAR T-cells mediated therapeutics. ENVIRONMENTAL RESEARCH 2023; 235:116573. [PMID: 37437865 DOI: 10.1016/j.envres.2023.116573] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/29/2023] [Accepted: 07/06/2023] [Indexed: 07/14/2023]
Abstract
Cancer is characterized by uncontrolled cell growth, disrupted regulatory pathways, and the accumulation of genetic mutations. These mutations across different types of cancer lead to disruptions in signaling pathways and alterations in protein expression related to cellular growth and proliferation. This review highlights the AKT signaling cascade and the retinoblastoma protein (pRb) regulating cascade as promising for novel nanotheranostic interventions. Through synergizing state-of-the-art gene editing tools like the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas system with nanomaterials and targeting AKT, there is potential to enhance cancer diagnostics significantly. Furthermore, the integration of modified CAR-T cells into multifunctional nanodelivery systems offers a promising approach for targeted cancer inhibition, including the eradication of cancer stem cells (CSCs). Within the context of highly aggressive and metastatic Triple-negative Breast Cancer (TNBC), this review specifically focuses on devising innovative nanotheranostics. For both pre-clinical and post-clinical TNBC detection, the utilization of the CRISPR-Cas system, guided by RNA (gRNA) and coupled with a fluorescent reporter specifically designed to detect TNBC's mutated sequence, could be promising. Additionally, a cutting-edge approach involving the engineering of TNBC-specific iCAR and syn-Notch CAR T-cells, combined with the co-delivery of a hybrid polymeric nano-liposome encapsulating a conditionally replicative adenoviral vector (CRAdV) against CSCs, could present an intriguing intervention strategy. This review thus paves the way for exciting advancements in the field of nanotheranostics for the treatment of TNBC and beyond.
Collapse
Affiliation(s)
- Vinayak Nayak
- Indian Council of Agricultural Research- National Institute on Foot and Mouth Disease- International Center for Foot and Mouth Disease, Bhubaneswar, Odisha, India
| | - Sushmita Patra
- Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi-Mumbai 410210, India
| | - Kshitij Rb Singh
- Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, 2-4 Hibikino, Wakamatsu, Kitakyushu, Japan.
| | - Bristy Ganguly
- Fish Health Management Division, ICAR-Central Institute of Freshwater Aquaculture, Bhubaneswar, Odisha, India
| | - Das Nishant Kumar
- PG Department of Biotechnology, Utkal University, Bhubaneswar, Odisha, India
| | - Deepak Panda
- PG Department of Biotechnology, Utkal University, Bhubaneswar, Odisha, India
| | - Ganesh Kumar Maurya
- Zoology Section, Mahila Mahavidyalaya, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Jay Singh
- Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Sanatan Majhi
- PG Department of Biotechnology, Utkal University, Bhubaneswar, Odisha, India
| | - Rohit Sharma
- Department of Rasa Shastra and Bhaishajya Kalpana, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Shyam S Pandey
- Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, 2-4 Hibikino, Wakamatsu, Kitakyushu, Japan.
| | - Ravindra Pratap Singh
- Department of Biotechnology, Indira Gandhi National Tribal University, Amarkantak, Madhya Pradesh, India.
| | - Rout George Kerry
- PG Department of Biotechnology, Utkal University, Bhubaneswar, Odisha, India.
| |
Collapse
|
|
21
|
Cheng D, Zhang Z, Mi Z, Tao W, Liu D, Fu J, Fan H. Deciphering the heterogeneity and immunosuppressive function of regulatory T cells in osteosarcoma using single-cell RNA transcriptome. Comput Biol Med 2023; 165:107417. [PMID: 37669584 DOI: 10.1016/j.compbiomed.2023.107417] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 08/03/2023] [Accepted: 08/28/2023] [Indexed: 09/07/2023]
Abstract
Osteosarcoma (OS) is a highly invasive malignant neoplasm with poor prognosis. The tumor microenvironment (TME) plays an essential role in the occurrence and development of OS. Regulatory T cells (Tregs) are known to facilitate immunosuppression, tumor progression, invasion, and metastasis. However, the effect of Tregs in the TME of OS remains unclear. In this study, single-cell RNA sequencing (scRNA-seq) data was used to identify Tregs and various other cell clusters in the TME of OS. Gene set variation analysis (GSVA) was used to investigate the signaling pathways in Tregs from OS and adjacent tissues. The CellChat and iTALK packages were used to analyze cellular communication. In addition, a prognostic model was established based on the Tregs-specific genes using bulk RNA-seq from the TARGET database, and it was verified using a Gene Expression Omnibus dataset. The pRRophetic package was used to predict drug sensitivity. Immunohistochemistry was used to verify the expression of candidate genes in OS. Based on the above methods, we showed that the OS samples were highly infiltrated with Tregs. GSVA revealed that oxidative phosphorylation, angiogenesis and mammalian target of rapamycin complex 1 (mTORC1) were highly activated in Tregs from OS compared with those from adjacent tissues. Using cellular communication analysis, we found that Tregs interacted with osteoblastic, endothelial, and myeloid cells via C-X-C motif chemokine ligand (CXCL) signaling; particularly, they strongly affected the expression of C-X-C motif chemokine receptor 4 (CXCR4) and interacted with other cell clusters through CXCL12/transforming growth factor β1 (TGFB1) to collectively enable tumor growth and progression. Subsequently, two Tregs-specific genes-CD320 and MAF-were screened through univariate, least absolute shrinkage and selection operator regression (LASSO) and multivariate analysis to construct a prognostic model, which showed excellent prognostic accuracy in two independent cohorts. In addition, drug sensitivity analysis demonstrated that OS patients at high Tregs risk were sensitive to sunitinib, sorafenib, and axitinib. We also used immunohistochemistry to validate that CD320 and MAF were significantly upregulated in OS tissues compared with adjacent tissues. Overall, this study reveals the heterogeneity of Tregs in the OS TME, providing new insights into the invasion and treatment of this cancer.
Collapse
Affiliation(s)
- Debin Cheng
- Department of Orthopaedic Surgery, Xi Jing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Zhao Zhang
- Department of Orthopaedic Surgery, Xi Jing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Zhenzhou Mi
- Department of Orthopaedic Surgery, Xi Jing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Weidong Tao
- Department of Orthopaedic Surgery, Xi Jing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Dong Liu
- Department of Orthopaedic Surgery, Xi Jing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Jun Fu
- Department of Orthopaedic Surgery, Xi Jing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Hongbin Fan
- Department of Orthopaedic Surgery, Xi Jing Hospital, The Fourth Military Medical University, Xi'an, China.
| |
Collapse
|
|
22
|
Bied M, Ho WW, Ginhoux F, Blériot C. Roles of macrophages in tumor development: a spatiotemporal perspective. Cell Mol Immunol 2023; 20:983-992. [PMID: 37429944 PMCID: PMC10468537 DOI: 10.1038/s41423-023-01061-6] [Citation(s) in RCA: 102] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 06/16/2023] [Indexed: 07/12/2023] Open
Abstract
Macrophages are critical regulators of tissue homeostasis but are also abundant in the tumor microenvironment (TME). In both primary tumors and metastases, such tumor-associated macrophages (TAMs) seem to support tumor development. While we know that TAMs are the dominant immune cells in the TME, their vast heterogeneity and associated functions are only just being unraveled. In this review, we outline the various known TAM populations found thus far and delineate their specialized roles associated with the main stages of cancer progression. We discuss how macrophages may prime the premetastatic niche to enable the growth of a metastasis and then how subsequent metastasis-associated macrophages can support secondary tumor growth. Finally, we speculate on the challenges that remain to be overcome in TAM research.
Collapse
Affiliation(s)
- Mathilde Bied
- Institut Gustave Roussy, INSERM U1015, Villejuif, France
| | - William W Ho
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Florent Ginhoux
- Institut Gustave Roussy, INSERM U1015, Villejuif, France.
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore.
- Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai, China.
- Translational Immunology Institute, SingHealth Duke-NUS, Singapore, Singapore.
| | - Camille Blériot
- Institut Gustave Roussy, INSERM U1015, Villejuif, France.
- Institut Necker des Enfants Malades, INSERM, CNRS, Université Paris Cité, Paris, France.
| |
Collapse
|
|
23
|
Sadri M, Najafi A, Rahimi A, Behranvand N, Hossein Kazemi M, Khorramdelazad H, Falak R. Hypoxia effects on oncolytic virotherapy in Cancer: Friend or Foe? Int Immunopharmacol 2023; 122:110470. [PMID: 37433246 DOI: 10.1016/j.intimp.2023.110470] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 06/06/2023] [Accepted: 06/07/2023] [Indexed: 07/13/2023]
Abstract
Researchers have tried to find novel strategies for cancer treatment in the past decades. Among the utilized methods, administering oncolytic viruses (OVs) alone or combined with other anticancer therapeutic approaches has had promising outcomes, especially in solid tumors. Infecting the tumor cells by these viruses can lead to direct lysis or induction of immune responses. However, the immunosuppressive tumor microenvironment (TME) is considered a significant challenge for oncolytic virotherapy in treating cancer. Based on OV type, hypoxic conditions in the TME can accelerate or repress virus replication. Therefore, genetic manipulation of OVs or other molecular modifications to reduce hypoxia can induce antitumor responses. Moreover, using OVs with tumor lysis capability in the hypoxic TME may be an attractive strategy to overcome the limitations of the therapy. This review summarizes the latest information available in the field of cancer virotherapy and discusses the dual effect of hypoxia on different types of OVs to optimize available related therapeutic methods.
Collapse
Affiliation(s)
- Maryam Sadri
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Najafi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Rahimi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Nafiseh Behranvand
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Kazemi
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Hossein Khorramdelazad
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
| | - Reza Falak
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
24
|
Zhang H, Cao K, Xiang J, Zhang M, Zhu M, Xi Q. Hypoxia induces immunosuppression, metastasis and drug resistance in pancreatic cancers. Cancer Lett 2023; 571:216345. [PMID: 37558084 DOI: 10.1016/j.canlet.2023.216345] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/26/2023] [Accepted: 08/04/2023] [Indexed: 08/11/2023]
Abstract
Pancreatic cancer is one of the common malignant tumors of the digestive system and is known as the "king of cancers". It is extremely difficult to diagnose at an early stage, the disease progresses rapidly, and the effect of chemotherapy and radiotherapy is poor, so the prognosis of pancreatic cancer patients is very poor. Numerous studies have suggested that hypoxia is closely related to the development and progression of pancreatic cancer. Inadequate blood supply and desmoplasia in the microenvironment of pancreatic cancer can result in its extreme hypoxia. This hypoxic microenvironment can further contribute to angiogenesis and desmoplasia. Hypoxia is mediated by the complex hypoxia inducible factor (HIF) signaling pathway and plays an important role in the formation of a highly immunosuppressive microenvironment and the metastasis of pancreatic cancer. Further work on the hypoxic microenvironment will help clarify the specific mechanisms of the role of hypoxia in pancreatic cancer and provide a basis for the realization of hypoxia-targeted therapeutic and diagnostic strategies.
Collapse
Affiliation(s)
- Huan Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
| | - Kailei Cao
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
| | - Jingrong Xiang
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
| | - Mengting Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
| | - Mengxin Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
| | - Qinhua Xi
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
| |
Collapse
|
|
25
|
Bandopadhyay S, Patranabis S. Mechanisms of HIF-driven immunosuppression in tumour microenvironment. J Egypt Natl Canc Inst 2023; 35:27. [PMID: 37646847 DOI: 10.1186/s43046-023-00186-z] [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: 06/19/2023] [Accepted: 08/12/2023] [Indexed: 09/01/2023] Open
Abstract
Hypoxia arises due to insufficient oxygen delivery to rapidly proliferating tumour cells that outpace the available blood supply. It is a characteristic feature of most solid tumour microenvironments and plays a critical role in regulating anti-tumour immunity, enhancing tumoral heterogeneity, and promoting therapeutic resistance and poor clinical outcomes. Hypoxia-inducible factors (HIFs) are the major hypoxia-responsive transcription factors that are activated under low oxygenation conditions and have been identified to drive multifunctional roles in tumour immune evasion. The HIF signalling network serves as an attractive target for targeted therapeutic approaches. This review aims to provide a comprehensive overview of the most crucial mechanisms by which HIF controls the expression of immunosuppressive molecules and immune checkpoints, disrupts cancer immunogenicity, and induces immunotherapeutic resistance.
Collapse
Affiliation(s)
| | - Somi Patranabis
- Amity Institute of Biotechnology, Amity University, Kolkata, West Bengal, India.
| |
Collapse
|
|
26
|
Guerra P, Martini A, Pontisso P, Angeli P. Novel Molecular Targets for Immune Surveillance of Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:3629. [PMID: 37509293 PMCID: PMC10377787 DOI: 10.3390/cancers15143629] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 07/06/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common and aggressive cancer with a high mortality rate. The incidence of HCC is increasing worldwide, and the lack of effective screening programs often results in delayed diagnosis, making it a challenging disease to manage. Immunotherapy has emerged as a promising treatment option for different kinds of cancers, with the potential to stimulate the immune system to target cancer cells. However, the current immunotherapeutic approaches for HCC have shown limited efficacy. Since HCC arises within a complex tumour microenvironment (TME) characterized by the presence of various immune and stromal cell types, the understanding of this interaction is crucial for the identification of effective therapy. In this review, we highlight recent advances in our understanding of the TME of HCC and the immune cells involved in anti-tumour responses, including the identification of new possible targets for immunotherapy. We illustrate a possible classification of HCC based on the tumour immune infiltration and give evidence about the role of SerpinB3, a serine protease inhibitor involved in the regulation of the immune response in different cancers.
Collapse
Affiliation(s)
- Pietro Guerra
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, 35122 Padova, Italy
| | - Andrea Martini
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, 35122 Padova, Italy
| | - Patrizia Pontisso
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, 35122 Padova, Italy
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, 35122 Padova, Italy
| |
Collapse
|
|
27
|
Ding Y, Gong Y, Zeng H, Song G, Yu Z, Fu B, Liu Y, Huang D, Zhong Y. ZNF765 is a prognostic biomarker of hepatocellular carcinoma associated with cell cycle, immune infiltration, m 6A modification, and drug susceptibility. Aging (Albany NY) 2023; 15:6179-6211. [PMID: 37400985 PMCID: PMC10373972 DOI: 10.18632/aging.204827] [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: 09/21/2022] [Accepted: 06/05/2023] [Indexed: 07/05/2023]
Abstract
Hepatocellular carcinoma (HCC) is an ongoing challenge worldwide. Zinc finger protein 765 (ZNF765) is an important zinc finger protein that is related to the permeability of the blood-tumor barrier. However, the role of ZNF765 in HCC is unclear. This study evaluated the expression of ZNF765 in hepatocellular carcinoma and the impact of its expression on patient prognosis based on The Cancer Genome Atlas (TCGA). Immunohistochemical assays (IHC) were used to examine protein expression. Besides, a colony formation assay was used to examine cell viability. We also explored the relationship between ZNF765 and chemokines in the HCCLM3 cells by qRT-PCR. Moreover, we examined the effect of ZNF765 on cell resistance by measurement of the maximum half-inhibitory concentration. Our research revealed that ZNF765 expression in HCC samples was higher than that in normal samples, whose upregulation was not conducive to the prognosis. The results of GO, KEGG, and GSEA showed that ZNF765 was associated with the cell cycle and immune infiltration. Furthermore, we confirmed that the expression of ZNF765 had a strong connection with the infiltration level of various immune cells, such as B cells, CD4+ T cells, macrophages, and neutrophils. In addition, we found that ZNF765 was associated with m6A modification, which may affect the progression of HCC. Finally, drug sensitivity testing found that patients with HCC were sensitive to 20 drugs when they expressed high levels of ZNF765. In conclusion, ZNF765 may be a prognostic biomarker related to cell cycle, immune infiltration, m6A modification, and drug sensitivity for hepatocellular carcinoma.
Collapse
Affiliation(s)
- Yongqi Ding
- Second Affiliated Hospital of Nanchang University, Nanchang, China
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Yiyang Gong
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Hong Zeng
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Gelin Song
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Zichuan Yu
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Bidong Fu
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Yue Liu
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Da Huang
- Department of Thyroid Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yanying Zhong
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Nanchang University, Nanchang, China
| |
Collapse
|
|
28
|
Xiao Z, Wang R, Wang X, Yang H, Dong J, He X, Yang Y, Guo J, Cui J, Zhou Z. Impaired function of dendritic cells within the tumor microenvironment. Front Immunol 2023; 14:1213629. [PMID: 37441069 PMCID: PMC10333501 DOI: 10.3389/fimmu.2023.1213629] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 06/13/2023] [Indexed: 07/15/2023] Open
Abstract
Dendritic cells (DCs), a class of professional antigen-presenting cells, are considered key factors in the initiation and maintenance of anti-tumor immunity due to their powerful ability to present antigen and stimulate T-cell responses. The important role of DCs in controlling tumor growth and mediating potent anti-tumor immunity has been demonstrated in various cancer models. Accordingly, the infiltration of stimulatory DCs positively correlates with the prognosis and response to immunotherapy in a variety of solid tumors. However, accumulating evidence indicates that DCs exhibit a significantly dysfunctional state, ultimately leading to an impaired anti-tumor immune response due to the effects of the immunosuppressive tumor microenvironment (TME). Currently, numerous preclinical and clinical studies are exploring immunotherapeutic strategies to better control tumors by restoring or enhancing the activity of DCs in tumors, such as the popular DC-based vaccines. In this review, an overview of the role of DCs in controlling tumor progression is provided, followed by a summary of the current advances in understanding the mechanisms by which the TME affects the normal function of DCs, and concluding with a brief discussion of current strategies for DC-based tumor immunotherapy.
Collapse
Affiliation(s)
- Zhihua Xiao
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Ruiqi Wang
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Xuyan Wang
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Haikui Yang
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Jiamei Dong
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Xin He
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Yang Yang
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Jiahao Guo
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Jiawen Cui
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Zhiling Zhou
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| |
Collapse
|
|
29
|
Mani N, Andrews D, Obeng RC. Modulation of T cell function and survival by the tumor microenvironment. Front Cell Dev Biol 2023; 11:1191774. [PMID: 37274739 PMCID: PMC10232912 DOI: 10.3389/fcell.2023.1191774] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 05/02/2023] [Indexed: 06/06/2023] Open
Abstract
Cancer immunotherapy is shifting paradigms in cancer care. T cells are an indispensable component of an effective antitumor immunity and durable clinical responses. However, the complexity of the tumor microenvironment (TME), which consists of a wide range of cells that exert positive and negative effects on T cell function and survival, makes achieving robust and durable T cell responses difficult. Additionally, tumor biology, structural and architectural features, intratumoral nutrients and soluble factors, and metabolism impact the quality of the T cell response. We discuss the factors and interactions that modulate T cell function and survive in the TME that affect the overall quality of the antitumor immune response.
Collapse
Affiliation(s)
- Nikita Mani
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Dathan Andrews
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, United States
| | - Rebecca C. Obeng
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, United States
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, United States
- University Hospitals Cleveland Medical Center, Cleveland, OH, United States
| |
Collapse
|
|
30
|
Su X, Wang G, Zheng S, Ge C, Kong F, Wang C. Comprehensive Explorations of CCL28 in Lung Adenocarcinoma Immunotherapy and Experimental Validation. J Inflamm Res 2023; 16:1325-1342. [PMID: 37006812 PMCID: PMC10065022 DOI: 10.2147/jir.s399193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 03/17/2023] [Indexed: 03/29/2023] Open
Abstract
Background Chemokines have been reported to play an important role in cancer immunotherapy. This study aimed to explore the chemokines involved in lung cancer immunotherapy. Methods All the public data were downloaded from The Cancer Genome Atlas Program database. Quantitative real time-PCR was used to detect the mRNA level of specific molecules and Western blot was used for the protein level. Other experiments used include luciferase reporter experiments, flow cytometric analysis, Chromatin immunoprecipitation assay, ELISA and co-cultured system. Results We found that the CCL7, CCL11, CCL14, CCL24, CCL25, CCL26, CCL28 had a higher level, while the CCL17, CCL23 had a lower level in immunotherapy non-responders. Also, we found that immunotherapy non-responders had a higher level of CD56dim NK cells, NK cells, Th1 cells, Th2 cells and Treg, yet a lower level of iDC and Th17 cells. Biological enrichment analysis indicated that in the patients with high Treg infiltration, the pathways of pancreas beta cells, KRAS signaling, coagulation, WNT BETA catenin signaling, bile acid metabolism, interferon alpha response, hedgehog signaling, PI3K/AKT/mTOR signaling, apical surface, myogenesis were significantly enriched in. CCL7, CCL11, CCL26 and CCL28 were selected for further analysis. Compared with the patients with high CCL7, CCL11, CCL26 and CCL28 expression, the patients with low CCL7, CCL11, CCL26 and CCL28 expression had a better performance of immunotherapy response and this effect might partly be due to Treg cells. Furthermore, biological exploration and clinical correlation of CCL7, CCL11, CCL26 and CCL28 were conducted, Finally, CCL28 was selected for validation. Experiments showed that under the hypoxia condition, HIF-1α was upregulated, which can directly bind to the promoter region of CCL28 and lead to its higher level. Also, CCL28 secreted by lung cancer cells could induce Tregs infiltration. Conclusion Our study provides a novel insight focused on the chemokines in lung cancer immunotherapy. Also, CCL28 was identified as an underlying biomarker for lung cancer immunotherapy.
Collapse
Affiliation(s)
- Xiangyu Su
- School of Medicine, Southeast University, Nanjing, 210009, People’s Republic of China
- Department of Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, People’s Republic of China
| | - Guoqing Wang
- Department of Pathology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, People’s Republic of China
| | - Shiya Zheng
- Department of Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, People’s Republic of China
| | - Chang Ge
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People’s Republic of China
| | - Fei Kong
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People’s Republic of China
| | - Cailian Wang
- School of Medicine, Southeast University, Nanjing, 210009, People’s Republic of China
- Department of Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, People’s Republic of China
- Correspondence: Cailian Wang, Email
| |
Collapse
|
|
31
|
Hu B, Qu C, Qi WJ, Liu CH, Xiu DR. Development and verification of the glycolysis-associated and immune-related prognosis signature for hepatocellular carcinoma. Front Genet 2022; 13:955673. [PMID: 36267406 PMCID: PMC9576873 DOI: 10.3389/fgene.2022.955673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 09/05/2022] [Indexed: 11/21/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC) refers to the malignant tumor associated with a high mortality rate. This work focused on identifying a robust tumor glycolysis-immune-related gene signature to facilitate the prognosis prediction of HCC cases. Methods: This work adopted t-SNE algorithms for predicting glycolysis status in accordance with The Cancer Genome Atlas (TCGA)-derived cohort transcriptome profiles. In addition, the Cox regression model was utilized together with LASSO to identify prognosis-related genes (PRGs). In addition, the results were externally validated with the International Cancer Genome Consortium (ICGC) cohort. Results: Accordingly, the glycolysis-immune-related gene signature, which consisted of seven genes, PSRC1, CHORDC1, KPNA2, CDCA8, G6PD, NEIL3, and EZH2, was constructed based on TCGA-HCC patients. Under a range of circumstances, low-risk patients had extended overall survival (OS) compared with high-risk patients. Additionally, the developed gene signature acted as the independent factor, which was significantly associated with clinical stage, grade, portal vein invasion, and intrahepatic vein invasion among HCC cases. In addition, as revealed by the receiver operating characteristic (ROC) curve, the model showed high efficiency. Moreover, the different glycolysis and immune statuses between the two groups were further revealed by functional analysis. Conclusion: Our as-constructed prognosis prediction model contributes to HCC risk stratification.
Collapse
|
|
32
|
Wang J, Jin Z, Wu G, Deng Z, Wang J, Xu B, Zhu H, Guo Y, Wen Z. Construction of a 3-mRNA hypoxia prognostic model to evaluate immune microenvironment in hepatocellular carcinoma. Medicine (Baltimore) 2022; 101:e30589. [PMID: 36181125 PMCID: PMC9524961 DOI: 10.1097/md.0000000000030589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Hypoxia is a key factor in the development of hepatocellular carcinoma (HCC), which is the most common primary liver cancer with poor prognosis. The current study aimed to identify the potential prognostic biomarkers of the hypoxia-associated gene signature in patients with HCC, and to further explore the relationship between hypoxia and immune infiltration. METHODS After the determination of differentially expressed genes (DEGs) using the HCC transcriptome data of The Cancer Genome Atlas database and hypoxia-related gene set, the prognosis-associated genes were identified using univariate Cox regression analysis. Then, the hypoxia prognosis model was established via multivariate Cox regression analysis, with functional annotation conducted using Gene Set Enrichment Analysis. CIBERSORT was utilized to analyze the degree of tumor immune invasion, and an International Cancer Genome Consortium cohort to verify the reliability of the prognosis model. Expression levels of hypoxia-associated genes were detected by real-time quantitative polymerase chain reaction in HCC samples. RESULTS 3 genes (ENO1, SAP30, and STC2) constructed the hypoxia prognosis model. The patients were subdivided into 2 groups based on median risk score, with a high hypoxic score indicating poor prognosis of HCC. The hypoxia signature could be employed as an independent prognostic factor in HCC. In addition, the proportion of macrophages was higher in the high-risk group. CONCLUSION The hypoxia-associated signature could be a potential prognostic marker of HCC and provides a different perspective for immunotherapy of HCC.
Collapse
Affiliation(s)
- Jue Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zongrui Jin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Guolin Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zhenfeng Deng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jilong Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Banghao Xu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Hai Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Ya Guo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zhang Wen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- *Correspondence: Zhang Wen, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuangyong Road 6#, Nanning, Guangxi 530021, China (e-mail: )
| |
Collapse
|
|
33
|
McRitchie BR, Akkaya B. Exhaust the exhausters: Targeting regulatory T cells in the tumor microenvironment. Front Immunol 2022; 13:940052. [PMID: 36248808 PMCID: PMC9562032 DOI: 10.3389/fimmu.2022.940052] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 09/14/2022] [Indexed: 12/14/2022] Open
Abstract
The concept of cancer immunotherapy has gained immense momentum over the recent years. The advancements in checkpoint blockade have led to a notable progress in treating a plethora of cancer types. However, these approaches also appear to have stalled due to factors such as individuals' genetic make-up, resistant tumor sub-types and immune related adverse events (irAE). While the major focus of immunotherapies has largely been alleviating the cell-intrinsic defects of CD8+ T cells in the tumor microenvironment (TME), amending the relationship between tumor specific CD4+ T cells and CD8+ T cells has started driving attention as well. A major roadblock to improve the cross-talk between CD4+ T cells and CD8+ T cells is the immune suppressive action of tumor infiltrating T regulatory (Treg) cells. Despite their indispensable in protecting tissues against autoimmune threats, Tregs have also been under scrutiny for helping tumors thrive. This review addresses how Tregs establish themselves at the TME and suppress anti-tumor immunity. Particularly, we delve into factors that promote Treg migration into tumor tissue and discuss the unique cellular and humoral composition of TME that aids survival, differentiation and function of intratumoral Tregs. Furthermore, we summarize the potential suppression mechanisms used by intratumoral Tregs and discuss ways to target those to ultimately guide new immunotherapies.
Collapse
Affiliation(s)
- Bayley R. McRitchie
- Department of Neurology, The College of Medicine, The Ohio State University, Columbus, OH, United States
- Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Billur Akkaya
- Department of Neurology, The College of Medicine, The Ohio State University, Columbus, OH, United States
- Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
- Department of Microbial Infection and Immunity, The College of Medicine, The Ohio State University, Columbus, OH, United States
| |
Collapse
|
|
34
|
Roles of CCR10/CCL27-CCL28 axis in tumour development: mechanisms, diagnostic and therapeutic approaches, and perspectives. Expert Rev Mol Med 2022; 24:e37. [PMID: 36155126 DOI: 10.1017/erm.2022.28] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Cancer is now one of the major causes of death across the globe. The imbalance of cytokine and chemokine secretion has been reported to be involved in cancer development. Meanwhile, CC chemokines have received considerable interest in cancer research. CCR10, as the latest identified CC chemokine receptor (CCR), has been implicated in the recruitment and infiltration of immune cells, especially lymphocytes, into epithelia such as skin via ligation to two ligands, CCL27 and CCL28. Other than homoeostatic function, several mechanisms have been shown to dysregulate CCR10/CCL27-CCL28 expression in the tumour microenvironment. As such, these receptors and ligands mediate T-cell trafficking in the tumour microenvironment. Depending on the types of lymphocytes recruited, CCR10/CCL27-CCL28 interaction has been shown to play conflicting roles in cancer development. If they were T helper and cytotoxic T cells and natural killer cells, the role of this axis would be tumour-suppressive. In contrast, if CCR10/CCL27-CCL28 recruited regulatory T cells, cancer-associated fibroblasts or myeloid-derived suppressor cells, it would lead to tumour progression. In addition to the trafficking of lymphocytes and immune cells, CCR10 also leads to the migration of tumour cells or endothelial cells (called angiogenesis and lymphangiogenesis) to promote tumour metastasis. Furthermore, CCR10 signalling triggers tumour-promoting signalling such as PI3K/AKT and mitogen-activated protein kinase/extracellular signal-regulated kinase, resulting in tumour cell growth. Since CCR10/CCL27-CCL28 is dysregulated in the tumour tissues, it is suggested that analysis and measurement of them might predict tumour development. Finally, it is hoped using therapeutic approaches based on this axis might increase our knowledge to overcome tumour progression.
Collapse
|
|
35
|
Laudanski K, Liu D, Okeke T, Restrepo M, Szeto WY. Persistent Depletion of Neuroprotective Factors Accompanies Neuroinflammatory, Neurodegenerative, and Vascular Remodeling Spectra in Serum Three Months after Non-Emergent Cardiac Surgery. Biomedicines 2022; 10:2364. [PMID: 36289630 PMCID: PMC9598177 DOI: 10.3390/biomedicines10102364] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 09/16/2022] [Accepted: 09/19/2022] [Indexed: 11/24/2022] Open
Abstract
We hypothesized that the persistent depletion of neuroprotective markers accompanies neuroinflammation and neurodegeneration in patients after cardiac surgery. A total of 158 patients underwent elective heart surgery with their blood collected before surgery (tbaseline) and 24 h (t24hr), seven days (t7d), and three months (t3m) post-surgery. The patients' serum was measured for markers of neurodegeneration (τau, τaup181-183, amyloid β1-40/β2-42, and S100), atypical neurodegeneration (KLK6 and NRGN), neuro-injury (neurofilament light/heavy, UC-HL, and GFAP), neuroinflammation (YKL-40 and TDP-43), peripheral nerve damage (NCAM-1), neuroprotection (apoE4, BDNF, fetuin, and clusterin), and vascular smoldering inflammation (C-reactive protein, CCL-28 IL-6, and IL-8). The mortality at 28 days, incidence of cerebrovascular accidents (CVA), and functional status were followed for three months. The levels of amyloid β1-40/β1-42 and NF-L were significantly elevated at all time points. The levels of τau, S100, KLK6, NRGN, and NCAM-1 were significantly elevated at 24 h. A cluster analysis demonstrated groupings around amyloids, KLK6, and NCAM-1. YKL-40, but not TDP-43, was significantly elevated across all time points. BDNF, apoE4, fetuin, and clusterin levels were significantly diminished long-term. IL-6 and IL-8 levles returned to baseline at t3m. The levels of CRP, CCL-28, and Hsp-70 remained elevated. At 3 months, 8.2% of the patients experienced a stroke, with transfusion volume being a significant variable. Cardiac-surgery patients exhibited persistent peripheral and neuronal inflammation, blood vessel remodeling, and the depletion of neuroprotective factors 3 months post-procedure.
Collapse
Affiliation(s)
- Krzysztof Laudanski
- Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA
- Leonard Davis Institute for Health Economics, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Da Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110055, China
| | - Tony Okeke
- Department of Bioengineering, Drexel University, Philadelphia, PA 19104, USA
| | - Mariana Restrepo
- College of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Wilson Y. Szeto
- Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA
| |
Collapse
|
|
36
|
Sahu A, Kose K, Kraehenbuehl L, Byers C, Holland A, Tembo T, Santella A, Alfonso A, Li M, Cordova M, Gill M, Fox C, Gonzalez S, Kumar P, Wang AW, Kurtansky N, Chandrani P, Yin S, Mehta P, Navarrete-Dechent C, Peterson G, King K, Dusza S, Yang N, Liu S, Phillips W, Guitera P, Rossi A, Halpern A, Deng L, Pulitzer M, Marghoob A, Chen CSJ, Merghoub T, Rajadhyaksha M. In vivo tumor immune microenvironment phenotypes correlate with inflammation and vasculature to predict immunotherapy response. Nat Commun 2022; 13:5312. [PMID: 36085288 PMCID: PMC9463451 DOI: 10.1038/s41467-022-32738-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 08/12/2022] [Indexed: 12/03/2022] Open
Abstract
Response to immunotherapies can be variable and unpredictable. Pathology-based phenotyping of tumors into ‘hot’ and ‘cold’ is static, relying solely on T-cell infiltration in single-time single-site biopsies, resulting in suboptimal treatment response prediction. Dynamic vascular events (tumor angiogenesis, leukocyte trafficking) within tumor immune microenvironment (TiME) also influence anti-tumor immunity and treatment response. Here, we report dynamic cellular-level TiME phenotyping in vivo that combines inflammation profiles with vascular features through non-invasive reflectance confocal microscopic imaging. In skin cancer patients, we demonstrate three main TiME phenotypes that correlate with gene and protein expression, and response to toll-like receptor agonist immune-therapy. Notably, phenotypes with high inflammation associate with immunostimulatory signatures and those with high vasculature with angiogenic and endothelial anergy signatures. Moreover, phenotypes with high inflammation and low vasculature demonstrate the best treatment response. This non-invasive in vivo phenotyping approach integrating dynamic vasculature with inflammation serves as a reliable predictor of response to topical immune-therapy in patients. Standard assessment of immune infiltration of biopsies is not sufficient to accurately predict response to immunotherapy. Here, the authors show that reflectance confocal microscopy can be used to quantify dynamic vasculature and inflammatory features to better predict treatment response in skin cancers.
Collapse
Affiliation(s)
- Aditi Sahu
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Kivanc Kose
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Lukas Kraehenbuehl
- Parker Institute for Cancer Immunotherapy, Ludwig Collaborative and Swim Across America Laboratory, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Candice Byers
- Roux Institute, Northeastern University, Portland, ME, USA.,Department of Electrical and Computer Engineering, Northeastern University, Boston, MA, USA
| | - Aliya Holland
- Parker Institute for Cancer Immunotherapy, Ludwig Collaborative and Swim Across America Laboratory, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Teguru Tembo
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.,SUNY Downstate Health Sciences University, Brooklyn, NY, USA
| | | | - Anabel Alfonso
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Madison Li
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Miguel Cordova
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Melissa Gill
- SUNY Downstate Health Sciences University, Brooklyn, NY, USA.,Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital Solna, Stockholm, Sweden.,Faculty of Medicine and Health Sciences, University of Alcala, Madrid, Spain
| | - Christi Fox
- Caliber Imaging and Diagnostics, Rochester, NY, USA
| | - Salvador Gonzalez
- Faculty of Medicine and Health Sciences, University of Alcala, Madrid, Spain
| | - Piyush Kumar
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | | | | | - Shen Yin
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Paras Mehta
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Cristian Navarrete-Dechent
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gary Peterson
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kimeil King
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Stephen Dusza
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ning Yang
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Shuaitong Liu
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Pascale Guitera
- Sydney Melanoma Diagnostic Center, Sydney, NSW, Australia.,Melanoma Institute Australia, Wollstonecraft, NSW, Australia
| | - Anthony Rossi
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Allan Halpern
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Liang Deng
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Weill Cornell Medicine, New York, NY, USA
| | | | | | | | - Taha Merghoub
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Parker Institute for Cancer Immunotherapy, Ludwig Collaborative and Swim Across America Laboratory, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Weill Cornell Medicine, New York, NY, USA
| | | |
Collapse
|
|
37
|
Zhang F, Liu H, Duan M, Wang G, Zhang Z, Wang Y, Qian Y, Yang Z, Jiang X. Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application. J Hematol Oncol 2022; 15:84. [PMID: 35794625 PMCID: PMC9258089 DOI: 10.1186/s13045-022-01304-5] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 06/09/2022] [Indexed: 12/13/2022] Open
Abstract
The tumor microenvironment (TME), which is regulated by intrinsic oncogenic mechanisms and epigenetic modifications, has become a research hotspot in recent years. Characteristic features of TME include hypoxia, metabolic dysregulation, and immunosuppression. One of the most common RNA modifications, N6-methyladenosine (m6A) methylation, is widely involved in the regulation of physiological and pathological processes, including tumor development. Compelling evidence indicates that m6A methylation regulates transcription and protein expression through shearing, export, translation, and processing, thereby participating in the dynamic evolution of TME. Specifically, m6A methylation-mediated adaptation to hypoxia, metabolic dysregulation, and phenotypic shift of immune cells synergistically promote the formation of an immunosuppressive TME that supports tumor proliferation and metastasis. In this review, we have focused on the involvement of m6A methylation in the dynamic evolution of tumor-adaptive TME and described the detailed mechanisms linking m6A methylation to change in tumor cell biological functions. In view of the collective data, we advocate treating TME as a complete ecosystem in which components crosstalk with each other to synergistically achieve tumor adaptive changes. Finally, we describe the potential utility of m6A methylation-targeted therapies and tumor immunotherapy in clinical applications and the challenges faced, with the aim of advancing m6A methylation research.
Collapse
|
|
38
|
Hu J, Li X, Yang L, Li H. Hypoxia, a key factor in the immune microenvironment. Biomed Pharmacother 2022; 151:113068. [PMID: 35676780 DOI: 10.1016/j.biopha.2022.113068] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/15/2022] [Accepted: 04/28/2022] [Indexed: 11/29/2022] Open
Abstract
The physical and chemical pressures in the tumor microenvironment (TME) play an important role in tumor development by regulating stromal elements, including immune cells. Hypoxia can induce a cascade of events in tumor initiation and development via immune regulation. As a dangerous factor, hypoxia activates multiple signaling pathways to reshape the immune microenvironment, leading to immunosuppression. Consequently, targeting hypoxia in the TME is a potential strategy to prevent immune escape and inhibit malignant tumor progression. In this review, we summarized the role of hypoxia-induced factors in the tumor immune escape process and provide a novel pathway to restrain tumor progression and development.
Collapse
Affiliation(s)
- Jingyao Hu
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang 110032, China.
| | - Xinyu Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang 110032, China.
| | - Liang Yang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang 110032, China.
| | - Hangyu Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang 110032, China.
| |
Collapse
|
|
39
|
Peripheral Blood Mononuclear Cells Predict Therapeutic Efficacy of Immunotherapy in NSCLC. Cancers (Basel) 2022; 14:cancers14122898. [PMID: 35740564 PMCID: PMC9221141 DOI: 10.3390/cancers14122898] [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: 05/09/2022] [Revised: 06/02/2022] [Accepted: 06/06/2022] [Indexed: 11/29/2022] Open
Abstract
Simple Summary Biomarkers to guide clinical decisions and efficacy are limited in advanced non-small cell lung cancer’s anti-PD-1 immune checkpoint inhibitors. We prospectively explored baseline peripheral blood mononuclear cells in order to asses’ immunotherapy predictors in this setting. We included 39 patients diagnosed with non-small cell lung cancer treated with immunotherapy in the study group and 40 patients with advanced malignancies treated with non-immunotherapy treatment, as control group. We detected that high baseline levels of circulating T cell subpopulations related to tissue lymphocyte recruitment are associated with poorer outcomes of immunotherapy-treated advanced non-small cell lung cancer patients, and these differences were specific to immunotherapy-treated patients. Abstract In lung cancer immunotherapy, biomarkers to guide clinical decisions are limited. We now explore whether the detailed immunophenotyping of circulating peripheral blood mononuclear cells (PBMCs) can predict the efficacy of anti-PD-1 immunotherapy in patients with advanced non-small-cell lung cancer (NSCLC). We determined 107 PBMCs subpopulations in a prospective cohort of NSCLC patients before starting single-agent anti-PD-1 immunotherapy (study group), analyzed by flow cytometry. As a control group, we studied patients with advanced malignancies before initiating non-immunotherapy treatment. The frequency of PBMCs was correlated with treatment outcome. Patients were categorized as having either high or low expression for each biomarker, defined as those above the 55th or below the 45th percentile of the overall marker expression within the cohort. In the study group, three subpopulations were associated with significant differences in outcome: high pretreatment levels of circulating CD4+CCR9+, CD4+CCR10+, or CD8+CXCR4+ T cells correlated with poorer overall survival (15.7 vs. 35.9 months, HR 0.16, p = 0.003; 22.0 vs. NR months, HR 0.10, p = 0.003, and 22.0 vs. NR months, HR 0.29, p = 0.02). These differences were specific to immunotherapy-treated patients. High baseline levels of circulating T cell subpopulations related to tissue lymphocyte recruitment are associated with poorer outcomes of immunotherapy-treated advanced NSCLC patients.
Collapse
|
|
40
|
Brajer-Luftmann B, Kaczmarek M, Nowicka A, Stelmach-Mardas M, Wyrzykiewicz M, Yasar S, Piorunek T, Sikora J, Batura-Gabryel H. Regulatory T cells, damage-associated molecular patterns, and myeloid-derived suppressor cells in bronchoalveolar lavage fluid interlinked with chronic obstructive pulmonary disease severity: An observational study. Medicine (Baltimore) 2022; 101:e29208. [PMID: 35687771 PMCID: PMC9276103 DOI: 10.1097/md.0000000000029208] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 05/17/2022] [Indexed: 01/04/2023] Open
Abstract
The role of regulatory T cells (Tregs), damage-associated molecular patterns (DAMPs), and myeloid-derived suppressor cells (MDSCs) in the mechanism of innate and adaptive immune responses in chronic obstructive pulmonary disease (COPD) is not well understood.Evaluating the presence of Tregs in the bronchoalveolar lavage fluid (BALF) and peripheral blood in patients with COPD, and assessment of the relationship between Tregs, MDSCs, and DAMPs as factors activating innate and adaptive immune responses. Description of the association between immune and clinical parameters in COPD.Thirty-one patients with COPD were enrolled. Clinical parameters (forced expiratory volume in one second [FEV1], forced vital capacity, total lung capacity [TLC], diffusion capacity of carbon monoxide, and B-BMI, O-obstruction, D-dyspnea, E-exercise [BODE]) were assessed. Tregs and MDSCs were investigated in the BALF and blood using monoclonal antibodies directly conjugated with fluorochromes in flow cytometry. The levels of defensin (DEF2), galectin-1 (Gal-1), galectin-3 (Gal-3), galectin-9 (Gal-9), heat shock protein-27 (HSP27), and surfactant protein A were assessed via sandwich enzyme-linked immunosorbent assay.The percentage of Tregs was significantly higher in the blood than in the BALF, in contrast to the mean fluorescence intensity of forkhead box P3 (FoxP3). Significant associations were observed between Tregs and HSP27 (r = 0.39), Gal-1 (r = 0.55), Gal-9 (r = -0.46), and MDSCs (r = -0.50), and between FoxP3 and Gal-1 (r = -0.42), Gal-3 (r = -0.39), and MDSCs (r = -0.43). Tregs and clinical parameters, including FEV1%pred (r = 0.39), residual volume (RV)%pred (r = -0.56), TLC%pred (r = -0.55), RV/TLC (r = -0.50), arterial oxygen saturation (r = -0.38), and arterial oxygen pressure (r = -0.39) were significantly correlated. FoxP3 was significantly interlinked with RV/TLC (r = -0.52), arterial oxygen pressure (r = 0.42), and BODE index (r = -0.57).The interaction between innate and adaptive immune responses in patients with COPD was confirmed. The expression of Tregs in BALF may have prognostic value in patients with COPD. The conversion of immune responses to clinical parameters appears to be associated with disease severity.
Collapse
Affiliation(s)
- Beata Brajer-Luftmann
- Department of Pulmonology, Allergology and Pulmonary Oncology, Poznan University of Medical Sciences, Szamarzewskiego 84 Street, Poznan, Poland
| | - Mariusz Kaczmarek
- Department of Cancer Immunology, Poznan University of Medical Sciences, Garbary 15 Street, Poznan, Poland
- Gene Therapy Laboratory, Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Centre, Garbary 15 Street, Poznan, Poland
| | - Agata Nowicka
- Department of Pulmonology, Allergology and Pulmonary Oncology, Poznan University of Medical Sciences, Szamarzewskiego 84 Street, Poznan, Poland
| | - Marta Stelmach-Mardas
- Department of Treatment of Obesity, Metabolic Disorders and Clinical Dietetics, Poznan University of Medical Sciences, Szamarzewskiego 84 Street, Poznan, Poland
| | - Magdalena Wyrzykiewicz
- Department of Clinical Immunology, Poznan University of Medical Sciences, Rokietnicka 5D Street, Poznan, Poland
| | - Senan Yasar
- The Christ Hospital Heart and Vascular Center, The Carl and Edyth Lindner Center for Research and Education, Cincinnati, OH
| | - Tomasz Piorunek
- Department of Pulmonology, Allergology and Pulmonary Oncology, Poznan University of Medical Sciences, Szamarzewskiego 84 Street, Poznan, Poland
| | - Jan Sikora
- Department of Clinical Immunology, Poznan University of Medical Sciences, Rokietnicka 5D Street, Poznan, Poland
| | - Halina Batura-Gabryel
- Department of Pulmonology, Allergology and Pulmonary Oncology, Poznan University of Medical Sciences, Szamarzewskiego 84 Street, Poznan, Poland
| |
Collapse
|
|
41
|
Wu Q, You L, Nepovimova E, Heger Z, Wu W, Kuca K, Adam V. Hypoxia-inducible factors: master regulators of hypoxic tumor immune escape. J Hematol Oncol 2022; 15:77. [PMID: 35659268 PMCID: PMC9166526 DOI: 10.1186/s13045-022-01292-6] [Citation(s) in RCA: 193] [Impact Index Per Article: 64.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Accepted: 05/17/2022] [Indexed: 12/12/2022] Open
Abstract
Hypoxia, a common feature of the tumor microenvironment in various types of cancers, weakens cytotoxic T cell function and causes recruitment of regulatory T cells, thereby reducing tumoral immunogenicity. Studies have demonstrated that hypoxia and hypoxia-inducible factors (HIFs) 1 and 2 alpha (HIF1A and HIF2A) are involved in tumor immune escape. Under hypoxia, activation of HIF1A induces a series of signaling events, including through programmed death receptor-1/programmed death ligand-1. Moreover, hypoxia triggers shedding of complex class I chain-associated molecules through nitric oxide signaling impairment to disrupt immune surveillance by natural killer cells. The HIF-1-galactose-3-O-sulfotransferase 1-sulfatide axis enhances tumor immune escape via increased tumor cell-platelet binding. HIF2A upregulates stem cell factor expression to recruit tumor-infiltrating mast cells and increase levels of cytokines interleukin-10 and transforming growth factor-β, resulting in an immunosuppressive tumor microenvironment. Additionally, HIF1A upregulates expression of tumor-associated long noncoding RNAs and suppresses immune cell function, enabling tumor immune escape. Overall, elucidating the underlying mechanisms by which HIFs promote evasion of tumor immune surveillance will allow for targeting HIF in tumor treatment. This review discusses the current knowledge of how hypoxia and HIFs facilitate tumor immune escape, with evidence to date implicating HIF1A as a molecular target in such immune escape. This review provides further insight into the mechanism of tumor immune escape, and strategies for tumor immunotherapy are suggested.
Collapse
Affiliation(s)
- Qinghua Wu
- College of Life Science, Yangtze University, Jingzhou, 434025, China.,Department of Chemistry, Faculty of Science, University of Hradec Kralove, 50003, Hradec Kralove, Czech Republic
| | - Li You
- College of Life Science, Yangtze University, Jingzhou, 434025, China
| | - Eugenie Nepovimova
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, 50003, Hradec Kralove, Czech Republic
| | - Zbynek Heger
- Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, 613 00, Czech Republic.,Central European Institute of Technology, Brno University of Technology, Brno, 602 00, Czech Republic
| | - Wenda Wu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China. .,Department of Chemistry, Faculty of Science, University of Hradec Kralove, 50003, Hradec Kralove, Czech Republic.
| | - Kamil Kuca
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, 50003, Hradec Kralove, Czech Republic.
| | - Vojtech Adam
- Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, 613 00, Czech Republic. .,Central European Institute of Technology, Brno University of Technology, Brno, 602 00, Czech Republic.
| |
Collapse
|
|
42
|
Zhao LP, Hu JH, Hu D, Wang HJ, Huang CG, Luo RH, Zhou ZH, Huang XY, Xie T, Lou JS. Hyperprogression, a challenge of PD-1/PD-L1 inhibitors treatments: potential mechanisms and coping strategies. Biomed Pharmacother 2022; 150:112949. [PMID: 35447545 DOI: 10.1016/j.biopha.2022.112949] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/01/2022] [Accepted: 04/08/2022] [Indexed: 11/29/2022] Open
Abstract
Immunotherapy is now a mainstay in cancer treatments. Programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) immune checkpoint inhibitor (ICI) therapies have opened up a new venue of advanced cancer immunotherapy. However, hyperprogressive disease (HPD) induced by PD-1/PD-L1 inhibitors caused a significant decrease in the overall survival (OS) of the patients, which compromise the efficacy of PD-1/PD-L1 inhibitors. Therefore, HPD has become an urgent issue to be addressed in the clinical uses of PD-1/PD-L1 inhibitors. The mechanisms of HPD remain unclear, and possible predictive factors of HPD are not well understood. In this review, we summarized the potential mechanisms of HPD and coping strategies that can effectively reduce the occurrence and development of HPD.
Collapse
Affiliation(s)
- Li-Ping Zhao
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Jun-Hu Hu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Die Hu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Hao-Jie Wang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Chang-Gang Huang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Ru-Hua Luo
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Zhao-Huang Zhou
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Xin-Yun Huang
- Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA.
| | - Tian Xie
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
| | - Jian-Shu Lou
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
| |
Collapse
|
|
43
|
Mudassar F, Shen H, Cook KM, Hau E. Improving the synergistic combination of programmed death‐1/programmed death ligand‐1 blockade and radiotherapy by targeting the hypoxic tumour microenvironment. J Med Imaging Radiat Oncol 2022; 66:560-574. [PMID: 35466515 PMCID: PMC9322583 DOI: 10.1111/1754-9485.13416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 04/05/2022] [Accepted: 04/10/2022] [Indexed: 11/28/2022]
Abstract
Immune checkpoint inhibition with PD‐1/PD‐L1 blockade is a promising area in the field of anti‐cancer therapy. Although clinical data have revealed success of PD‐1/PD‐L1 blockade as monotherapy or in combination with CTLA‐4 or chemotherapy, the combination with radiotherapy could further boost anti‐tumour immunity and enhance clinical outcomes due to the immunostimulatory effects of radiation. However, the synergistic combination of PD‐1/PD‐L1 blockade and radiotherapy can be challenged by the complex nature of the tumour microenvironment (TME), including the presence of tumour hypoxia. Hypoxia is a major barrier to the effectiveness of both radiotherapy and PD‐1/PD‐L1 blockade immunotherapy. Thus, targeting the hypoxic TME is an attractive strategy to enhance the efficacy of the combination. Addition of compounds that directly or indirectly reduce hypoxia, to the combination of PD‐1/PD‐L1 inhibitors and radiotherapy may optimize the success of the combination and improve therapeutic outcomes. In this review, we will discuss the synergistic combination of PD‐1/PD‐L1 blockade and radiotherapy and highlight the role of hypoxic TME in impeding the success of both therapies. In addition, we will address the potential approaches for targeting tumour hypoxia and how exploiting these strategies could benefit the combination of PD‐1/PD‐L1 blockade and radiotherapy.
Collapse
Affiliation(s)
- Faiqa Mudassar
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research The Westmead Institute for Medical Research Sydney New South Wales Australia
- Sydney Medical School The University of Sydney Sydney New South Wales Australia
| | - Han Shen
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research The Westmead Institute for Medical Research Sydney New South Wales Australia
- Sydney Medical School The University of Sydney Sydney New South Wales Australia
| | - Kristina M Cook
- Sydney Medical School The University of Sydney Sydney New South Wales Australia
- Charles Perkins Centre The University of Sydney Sydney New South Wales Australia
| | - Eric Hau
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research The Westmead Institute for Medical Research Sydney New South Wales Australia
- Sydney Medical School The University of Sydney Sydney New South Wales Australia
- Department of Radiation Oncology, Crown Princess Mary Cancer Centre Westmead Hospital Sydney New South Wales Australia
- Blacktown Hematology and Cancer Centre Blacktown Hospital Sydney New South Wales Australia
| |
Collapse
|
|
44
|
Parafiniuk K, Skiba W, Pawłowska A, Suszczyk D, Maciejczyk A, Wertel I. The Role of the Adipokine Resistin in the Pathogenesis and Progression of Epithelial Ovarian Cancer. Biomedicines 2022; 10:920. [PMID: 35453670 PMCID: PMC9028191 DOI: 10.3390/biomedicines10040920] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 04/14/2022] [Accepted: 04/15/2022] [Indexed: 02/07/2023] Open
Abstract
Obesity is a civilization disease associated with an increased risk of developing cardiovascular diseases, diabetes, and some malignancies. The results concerning the relationship between obesity and epithelial ovarian cancer (EOC) are inconclusive. The higher incidence of neoplasms in obese subjects has led to the development of the adipokine hypothesis. Omental adipocyte cells interact with cancer cells, promoting their migration and metastasis via the secretion of adipokines, growth factors, and hormones. One of the adipokines is resistin. It was shown in vitro that resistin stimulates the growth and differentiation of ovarian cancer cells. Moreover, it increases the level of angiogenesis factors, e.g., matrix metalloproteinase 2 (MMP-2) and vascular epithelial growth factor (VEGF). Additionally, resistin induces epithelial-mesenchymal transition (EMT) and stemness in EOC cell lines. A positive correlation has been shown between a higher level of resistin expression and the stage of histological differentiation of EOC or the occurrence of lymph node metastases. In addition, the overexpression of resistin has been found to act as an independent factor determining disease-free survival as well as overall survival in EOC patients. Growing evidence supports the finding that resistin plays an important role in some mechanisms leading to the progression of EOC, though this issue still requires further research.
Collapse
Affiliation(s)
- Klaudia Parafiniuk
- Independent Laboratory of Cancer Diagnostics and Immunology, Department of Oncological Gynaecology and Gynaecology, Faculty of Medicine, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland; (K.P.); (A.P.); (D.S.); (A.M.); (I.W.)
| | - Wiktoria Skiba
- Independent Laboratory of Cancer Diagnostics and Immunology, Department of Oncological Gynaecology and Gynaecology, Faculty of Medicine, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland; (K.P.); (A.P.); (D.S.); (A.M.); (I.W.)
| | - Anna Pawłowska
- Independent Laboratory of Cancer Diagnostics and Immunology, Department of Oncological Gynaecology and Gynaecology, Faculty of Medicine, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland; (K.P.); (A.P.); (D.S.); (A.M.); (I.W.)
| | - Dorota Suszczyk
- Independent Laboratory of Cancer Diagnostics and Immunology, Department of Oncological Gynaecology and Gynaecology, Faculty of Medicine, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland; (K.P.); (A.P.); (D.S.); (A.M.); (I.W.)
| | - Aleksandra Maciejczyk
- Independent Laboratory of Cancer Diagnostics and Immunology, Department of Oncological Gynaecology and Gynaecology, Faculty of Medicine, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland; (K.P.); (A.P.); (D.S.); (A.M.); (I.W.)
- Department of Functional Anatomy and Cytobiology, Institute of Biological Sciences, Maria Curie-Sklodowska University, Akademicka 19, 20-033 Lublin, Poland
| | - Iwona Wertel
- Independent Laboratory of Cancer Diagnostics and Immunology, Department of Oncological Gynaecology and Gynaecology, Faculty of Medicine, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland; (K.P.); (A.P.); (D.S.); (A.M.); (I.W.)
| |
Collapse
|
|
45
|
Mylod E, Lysaght J, Conroy MJ. Natural killer cell therapy: A new frontier for obesity-associated cancer. Cancer Lett 2022; 535:215620. [PMID: 35283210 DOI: 10.1016/j.canlet.2022.215620] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 02/16/2022] [Accepted: 03/03/2022] [Indexed: 02/09/2023]
Abstract
Natural killer (NK) cell infiltration of solid tumours is associated with better outcomes, placing augmentation of NK cell abundance in tumours as an attractive immunotherapeutic approach. The unique ability of NK cells to target cancer cells without antigen specificity increases their versatility and applicability as an immunotherapeutic tool. However, successful utilisation of NK cell-based therapies in solid tumours is still at an early stage. Obesity has become a global health epidemic, and the prevalence of obesity-associated cancers has significantly increased. Obesity-associated malignancies provide a unique challenge for the successful application of cell-based immunotherapies including NK cell-based therapies because significant numbers of NK and T cells are recruited to the visceral adipose tissue at the expense of successful tumour infiltration and eradication. As such, immunotherapy efficacy has been disappointing for obesity-associated malignancies such as oesophageal and gastric adenocarcinoma. Therefore, immunotherapies for obesity-associated cancers warrant our further attention. Indeed, it is becoming ever more obvious that more innovative approaches are needed to re-invigorate anti-tumour immunity and overcome immune exclusion in such tumours. In this review, we briefly summarise the dysfunctionality of NK cells in obesity-associated cancer. We outline the NK cell-based immunotherapeutic approaches which hold promise as effective treatments in this disease space, including CAR-NK cells. Furthermore, we suggest future avenues which possess the potential to transform immunotherapy and specifically NK cell therapy efficacy for obesity-associated cancer.
Collapse
Affiliation(s)
- Eimear Mylod
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute and Trinity St. James's Cancer Institute, St. James's Hospital, Trinity College Dublin, Dublin, 8, Ireland
| | - Joanne Lysaght
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute and Trinity St. James's Cancer Institute, St. James's Hospital, Trinity College Dublin, Dublin, 8, Ireland
| | - Melissa J Conroy
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute and Trinity St. James's Cancer Institute, St. James's Hospital, Trinity College Dublin, Dublin, 8, Ireland; Cancer Immunology Research Group, Department of Physiology, School of Medicine, Trinity College Dublin, Dublin, 2, Ireland.
| |
Collapse
|
|
46
|
Tan LY, Cockshell MP, Moore E, Myo Min KK, Ortiz M, Johan MZ, Ebert B, Ruszkiewicz A, Brown MP, Ebert LM, Bonder CS. Vasculogenic mimicry structures in melanoma support the recruitment of monocytes. Oncoimmunology 2022; 11:2043673. [PMID: 35295096 PMCID: PMC8920250 DOI: 10.1080/2162402x.2022.2043673] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The progression of cancer is facilitated by infiltrating leukocytes which can either actively kill cancer cells or promote their survival. Our current understanding of leukocyte recruitment into tumors is largely limited to the adhesion molecules and chemokines expressed by conventional blood vessels that are lined by endothelial cells (ECs). However, cancer cells themselves can form their own vascular structures (a process known as vasculogenic mimicry (VM)); but whether they actively participate in the recruitment of leukocytes remains to be elucidated. Herein, we demonstrate that VM-competent human melanoma cell lines express multiple adhesion molecules (e.g. CD44, intercellular adhesion molecule (ICAM)-1 and junction adhesion molecules (JAMs)) and chemokines (e.g. CXCL8 and CXCL12) relevant for leukocyte recruitment. Microfluidic-based adhesion assays revealed that similar to ECs, VM-competent melanoma cells facilitate the rolling and adhesion of leukocytes, particularly monocytes, under conditions of shear flow. Moreover, we identified ICAM-1 to be a key participant in this process. Transwell assays showed that, similar to ECs, VM-competent melanoma cells facilitate monocyte transmigration toward a chemotactic gradient. Gene expression profiling of human melanoma patient samples confirmed the expression of numerous leukocyte capture adhesion molecules and chemokines. Finally, immunostaining of patient tissue microarrays revealed that tumors with high VM content also contained higher numbers of leukocytes (including macrophages). Taken together, this study suggests an underappreciated role of VM vessels in solid tumors via their active participation in leukocyte recruitment and begins to identify key adhesion molecules and chemokines that underpin this process.
Collapse
Affiliation(s)
- Lih Y. Tan
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
| | - Michaelia P. Cockshell
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
| | - Eli Moore
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
| | - Kay K. Myo Min
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
| | - Michael Ortiz
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
| | - M. Zahied Johan
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
| | - Brenton Ebert
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
| | - Andrew Ruszkiewicz
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
| | - Michael P. Brown
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
- Adelaide Medical School, University of Adelaide, Adelaide, Australia
- Royal Adelaide Hospital, Cancer Clinical Trials Unit, Adelaide, Australia
| | - Lisa M. Ebert
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
- Adelaide Medical School, University of Adelaide, Adelaide, Australia
- Royal Adelaide Hospital, Cancer Clinical Trials Unit, Adelaide, Australia
| | - Claudine S. Bonder
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
- Adelaide Medical School, University of Adelaide, Adelaide, Australia
| |
Collapse
|
|
47
|
Wilczyński JR, Wilczyński M, Paradowska E. Cancer Stem Cells in Ovarian Cancer-A Source of Tumor Success and a Challenging Target for Novel Therapies. Int J Mol Sci 2022; 23:ijms23052496. [PMID: 35269636 PMCID: PMC8910575 DOI: 10.3390/ijms23052496] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 02/20/2022] [Accepted: 02/22/2022] [Indexed: 02/04/2023] Open
Abstract
Ovarian cancer is the most lethal neoplasm of the female genital organs. Despite indisputable progress in the treatment of ovarian cancer, the problems of chemo-resistance and recurrent disease are the main obstacles for successful therapy. One of the main reasons for this is the presence of a specific cell population of cancer stem cells. The aim of this review is to show the most contemporary knowledge concerning the biology of ovarian cancer stem cells (OCSCs) and their impact on chemo-resistance and prognosis in ovarian cancer patients, as well as to present the treatment options targeted exclusively on the OCSCs. The review presents data concerning the role of cancer stem cells in general and then concentrates on OCSCs. The surface and intracellular OCSCs markers and their meaning both for cancer biology and clinical prognosis, signaling pathways specifically activated in OCSCs, the genetic and epigenetic regulation of OCSCs function including the recent studies on the non-coding RNA regulation, cooperation between OCSCs and the tumor microenvironment (ovarian cancer niche) including very specific environment such as ascites fluid, the role of shear stress, autophagy and metabolic changes for the function of OCSCs, and finally mechanisms of OCSCs escape from immune surveillance, are described and discussed extensively. The possibilities of anti-OCSCs therapy both in experimental settings and in clinical trials are presented, including the recent II phase clinical trials and immunotherapy. OCSCs are a unique population of cancer cells showing a great plasticity, self-renewal potential and resistance against anti-cancer treatment. They are responsible for the progression and recurrence of the tumor. Several completed and ongoing clinical trials have tested different anti-OCSCs drugs which, however, have shown unsatisfactory efficacy in most cases. We propose a novel approach to ovarian cancer diagnosis and therapy.
Collapse
Affiliation(s)
- Jacek R Wilczyński
- Department of Gynecological Surgery and Gynecological Oncology, Medical University of Lodz, 4 Kosciuszki Str., 90-419 Lodz, Poland
- Correspondence:
| | - Miłosz Wilczyński
- Department of Gynecological, Endoscopic and Oncological Surgery, Polish Mother’s Health Center—Research Institute, 281/289 Rzgowska Str., 93-338 Lodz, Poland;
- Department of Surgical and Endoscopic Gynecology, Medical University of Lodz, 4 Kosciuszki Str., 90-419 Lodz, Poland
| | - Edyta Paradowska
- Laboratory of Virology, Institute of Medical Biology of the Polish Academy of Sciences, 106 Lodowa Str., 93-232 Lodz, Poland;
| |
Collapse
|
|
48
|
Cowman SJ, Koh MY. Revisiting the HIF switch in the tumor and its immune microenvironment. Trends Cancer 2022; 8:28-42. [PMID: 34743924 PMCID: PMC8702465 DOI: 10.1016/j.trecan.2021.10.004] [Citation(s) in RCA: 115] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 01/03/2023]
Abstract
Hypoxia is a hallmark of all solid tumors and their metastases. This leads to activation of the hypoxia-inducible factor (HIF) family of transcription factors, which modulate gene expression within both tumor cells and immune cells within the tumor microenvironment, influencing tumor progression and treatment response. The best characterized HIF isoforms, HIF-1α and HIF-2α, show nonoverlapping and often antagonistic roles. With the recent availability of inhibitors that target one or both HIFs, including the first-in-class selective HIF-2α inhibitor belzutifan, the prospect of HIF-α isoform-selective targeting is now a reality. Here, we summarize current knowledge on the unique contributions of the two HIF-α isoforms to tumor progression in the context of the complex tumor immune microenvironment, highlighting important considerations for therapy.
Collapse
Affiliation(s)
| | - Mei Yee Koh
- University of Utah, Salt Lake City, UT 84112, USA.
| |
Collapse
|
|
49
|
Cancer stem cells in hepatocellular carcinoma - from origin to clinical implications. Nat Rev Gastroenterol Hepatol 2022; 19:26-44. [PMID: 34504325 DOI: 10.1038/s41575-021-00508-3] [Citation(s) in RCA: 239] [Impact Index Per Article: 79.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/26/2021] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is an aggressive disease with a poor clinical outcome. The cancer stem cell (CSC) model states that tumour growth is powered by a subset of tumour stem cells within cancers. This model explains several clinical observations in HCC (as well as in other cancers), including the almost inevitable recurrence of tumours after initial successful chemotherapy and/or radiotherapy, as well as the phenomena of tumour dormancy and treatment resistance. The past two decades have seen a marked increase in research on the identification and characterization of liver CSCs, which has encouraged the design of novel diagnostic and treatment strategies for HCC. These studies revealed novel aspects of liver CSCs, including their heterogeneity and unique immunobiology, which are suggestive of opportunities for new research directions and potential therapies. In this Review, we summarize the present knowledge of liver CSC markers and the regulators of stemness in HCC. We also comprehensively describe developments in the liver CSC field with emphasis on experiments utilizing single-cell transcriptomics to understand liver CSC heterogeneity, lineage-tracing and cell-ablation studies of liver CSCs, and the influence of the CSC niche and tumour microenvironment on liver cancer stemness, including interactions between CSCs and the immune system. We also discuss the potential application of liver CSC-based therapies for treatment of HCC.
Collapse
|
|
50
|
Yan J, Yuan P, Gui L, Wang Z, Yin P, Gao WQ, Ma B. CCL28 Downregulation Attenuates Pancreatic Cancer Progression Through Tumor Cell-Intrinsic and -Extrinsic Mechanisms. Technol Cancer Res Treat 2021; 20:15330338211068958. [PMID: 34939465 PMCID: PMC8721394 DOI: 10.1177/15330338211068958] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
C-C motif chemokine ligand 28 (CCL28) has been reported to be pro-tumoral in several cancer types. However, the role of CCL28 in pancreatic ductal adenocarcinoma (PDAC) progression remains unclear. CCL28 mRNA expression in tumors from PDAC patients was found to be elevated as compared to normal pancreas. CCL28 expression was also negatively correlated with overall survival (OS) in pancreatic cancer patients. Our in vitro experiments showed that CCL28 knockdown impairs the proliferation of mouse pancreatic cancer cell line PAN02. Moreover, in both immunocompetent syngeneic mice and immunodeficient NOD-SCID mice, CCL28 deficiency significantly attenuated the growth of subcutaneous PAN02 tumors. In syngeneic mouse model, CCL28 downregulation remodeled the pancreatic tumor microenvironment by suppressing the infiltration of both regulatory T (Treg) cells, myeloid-derived suppressor cells, and activated pancreatic stellate cells, and upregulating the expression of lymphocyte cytotoxic proteins including perforin and granzyme B. In conclusion, our work demonstrates that CCL28 is a potential target for pancreatic cancer treatment and CCL28 blockade could inhibit tumor growth through both tumor-cell-intrinsic and extrinsic mechanisms.
Collapse
Affiliation(s)
- Jingjing Yan
- School of Biomedical Engineering, Med-X Research Institute, 12474Shanghai Jiao Tong University, Shanghai, China
| | - Pengkun Yuan
- School of Biomedical Engineering, Med-X Research Institute, 12474Shanghai Jiao Tong University, Shanghai, China
| | - Liming Gui
- School of Biomedical Engineering, Med-X Research Institute, 12474Shanghai Jiao Tong University, Shanghai, China
| | - Zhixue Wang
- School of Biomedical Engineering, Med-X Research Institute, 12474Shanghai Jiao Tong University, Shanghai, China
| | - Pan Yin
- School of Biomedical Engineering, Med-X Research Institute, 12474Shanghai Jiao Tong University, Shanghai, China
| | - Wei-Qiang Gao
- School of Biomedical Engineering, Med-X Research Institute, 12474Shanghai Jiao Tong University, Shanghai, China.,Clinical Stem Cell Research Center, Renji Hospital, School of Medicine, 12474Shanghai Jiao Tong University, Shanghai, China
| | - Bin Ma
- School of Biomedical Engineering, Med-X Research Institute, 12474Shanghai Jiao Tong University, Shanghai, China.,Clinical Stem Cell Research Center, Renji Hospital, School of Medicine, 12474Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|