|
1
|
Liu Q, Song M, Wang Y, Zhang P, Zhang H. CCL20-CCR6 signaling in tumor microenvironment: Functional roles, mechanisms, and immunotherapy targeting. Biochim Biophys Acta Rev Cancer 2025; 1880:189341. [PMID: 40348067 DOI: 10.1016/j.bbcan.2025.189341] [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: 10/15/2024] [Revised: 05/01/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025]
Abstract
Chemokine CC motif ligand 20 (CCL20) is a molecule with immunomodulatory properties that is involved in the regulation of diseases such as chronic inflammation, autoimmune diseases, and cancer. It operates by binding to its specific receptor, CC chemokine receptor type 6 (CCR6), and activating a complex intracellular signaling network. Building on its established role in inflammatory diseases, recent research has expanded our understanding of CCL20 to encompass its critical contributions to the tumor microenvironment (TME), highlighting its significance in cancer progression. Numerous studies have emphasized its prominent role in regulating immune responses. Consequently, Monoclonal antibodies against CCL20 and inhibitors of CCR6 have been successfully developed to block downstream signaling, making the CCL20-CCR6 axis a promising and critical target in the TME. This offers potential immunotherapeutic strategies for cancers. In this review, we summarize the biological consequences of CCL20-CCR6 mediated signaling, its role and mechanisms in the TME, and its potential applications. We suggest that the CCL20-CCR6 axis may be a novel biomarker for tumor diagnosis and prognosis, as well as a therapeutic target in various cancers.
Collapse
Affiliation(s)
- Qi Liu
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Mingyuan Song
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Yan Wang
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
| | - Ping Zhang
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Hao Zhang
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China.
| |
Collapse
|
|
2
|
Martínez-Ríos J, López-Pacheco CP, García-Zepeda EA, Soldevila G. CCR9 shapes the immune microenvironment of colorectal cancer modulating the balance between intratumoral CD8+ T cell and FoxP3+ Helios+ Treg subpopulations. PLoS One 2025; 20:e0321930. [PMID: 40305493 PMCID: PMC12043142 DOI: 10.1371/journal.pone.0321930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 03/12/2025] [Indexed: 05/02/2025] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer in the world and the second cause of death related to cancer. Regulatory T cell (Treg) infiltration is enriched in several tumor types including CRC and correlates with suppression of the anti-tumor immune response. In the large intestine, thymic Tregs (tTregs Helios+) and peripheral Tregs (pTregs Helios-) coexist and maintain intestinal homeostasis under steady state conditions. The recruitment of Treg cells to the intestine is orchestrated by the CCR9/CCL25 axis, which is potentiated under inflammatory conditions. Interestingly, the balance between cytotoxic CD8+ T cells and Tregs within the tumor microenvironment is critical for antitumor immunity and cancer progression. An elevated CD8+/Treg ratio has been associated with improved clinical outcomes in various cancers, including CRC. Therefore, here we investigate the potential role of chemokine receptor CCR9 on CD8+/Treg ratio and the effect of the recruitment of Treg subpopulations (Helios+ and Helios-) into the tumor microenvironment using the AOM/DSS induced colitis-associated colorectal cancer murine model. Our findings reveal that CCR9 deficiency leads to distinct alterations in the CRC microenvironment, characterized by decreased intratumoral Tregs Helios+. Also, the lack of the receptor leads to an improvement of the antitumor immune response, increasing the CD8+/Treg ratio within the tumor immune infiltrate. These results underscore the importance of CCR9 in shaping the immune microenvironment during CRC development.
Collapse
Affiliation(s)
- Jacobo Martínez-Ríos
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Cynthia Paola López-Pacheco
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Investigadora por México, Secretaría de Ciencia Tecnología y Humanidades (SECIHTI), Mexico City, Mexico
| | - Eduardo Alberto García-Zepeda
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Gloria Soldevila
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Laboratorio Nacional de Citometría de Flujo, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| |
Collapse
|
|
3
|
Ryba-Stanisławowska M. Unraveling Th subsets: insights into their role in immune checkpoint inhibitor therapy. Cell Oncol (Dordr) 2025; 48:295-312. [PMID: 39325360 PMCID: PMC11996958 DOI: 10.1007/s13402-024-00992-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/13/2024] [Indexed: 09/27/2024] Open
Abstract
T helper (Th) cell subsets play pivotal roles in regulating immune responses within the tumor microenvironment, influencing both tumor progression and anti-tumor immunity. Among these subsets, Th1 cells promote cytotoxic responses through the production of IFN-γ, while Th2 cells and regulatory T cells (Tregs) exert immunosuppressive effects that support tumor growth. Th9 and Th17 cells have context-dependent roles, contributing to both pro-inflammatory and regulatory processes in tumor immunity. Tumor antigen-specific T cells within the tumor microenvironment often exhibit a dysfunctional phenotype due to increased expression of inhibitory receptors such as CTLA-4 and PD-1, leading to reduced antitumor activity. Monoclonal antibodies that block these inhibitory signals-collectively known as immune checkpoint inhibitors (ICIs)-can reactivate these T cells, enhancing their ability to target and destroy cancer cells. Recent advancements have highlighted the critical role of T helper subsets in modulating responses to ICIs, with their interactions remaining a focus of ongoing research. Both positive and negative effects of ICIs have been reported in relation to Th cell subsets, with some effects depending on the type of tumor microenvironment. This review summarizes the crucial roles of different T helper cell subsets in tumor immunity and their complex relationship with immune checkpoint inhibitor therapy.
Collapse
Affiliation(s)
- Monika Ryba-Stanisławowska
- Department of Medical Immunology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 1, Gdańsk, 80-211, Poland.
| |
Collapse
|
|
4
|
Meyiah A, Khan FI, Alfaki DA, Murshed K, Raza A, Elkord E. The colorectal cancer microenvironment: Preclinical progress in identifying targets for cancer therapy. Transl Oncol 2025; 53:102307. [PMID: 39904281 PMCID: PMC11846588 DOI: 10.1016/j.tranon.2025.102307] [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: 11/06/2024] [Revised: 01/29/2025] [Accepted: 01/30/2025] [Indexed: 02/06/2025] Open
Abstract
Colorectal cancer (CRC) is a common cancer with high mortality rates. Despite progress in treatment, it remains an incurable disease for many patients. In CRC, the tumor microenvironment (TME) plays critical roles in tumor growth, progression, patients' prognosis, and response to treatments. Understanding TME complexities is important for developing effective therapies. In vitro and in vivo preclinical models are critical in understanding the disease, discovering potential targets, and developing effective therapeutics. In this review, we focus on preclinical research studies associated with modulation of the TME in CRC. These models give insights into understanding the role of stroma and immune cell components of the TME in CRC and improve clinical responses, providing insights in novel treatment options. Various studies have focused on targeting the TME in CRC to improve responses to different therapeutic approaches. These include identifying targets for cancer therapies, targeting molecular signaling, and enhancing the efficacy of immunotherapeutic modalities. Furthermore, targeting stromal and angiogenic factors in the TME may provide new therapeutic options. Overall, understanding and targeting the TME in CRC is a promising approach for improving therapeutic outcomes.
Collapse
Affiliation(s)
- Abdo Meyiah
- Department of Biosciences and Bioinformatics & Suzhou Municipal Key Lab of Biomedical Sciences and Translational Immunology, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Faez Iqbal Khan
- Department of Biosciences and Bioinformatics & Suzhou Municipal Key Lab of Biomedical Sciences and Translational Immunology, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Dia Aldeen Alfaki
- Department of Haematology, Al-Zaeim Al-Azhari University, Khartoum, Sudan
| | - Khaled Murshed
- Department of Pathology, Hamad Medical Corporation, Doha, Qatar
| | - Afsheen Raza
- College of Health Sciences, Abu Dhabi University, Abu Dhabi, United Arab Emirates
| | - Eyad Elkord
- Department of Biosciences and Bioinformatics & Suzhou Municipal Key Lab of Biomedical Sciences and Translational Immunology, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China; College of Health Sciences, Abu Dhabi University, Abu Dhabi, United Arab Emirates; Biomedical Research Center, School of Science, Engineering and Environment, University of Salford, Manchester, UK.
| |
Collapse
|
|
5
|
Zhai Y, Liang X, Deng M. Myeloid cells meet CD8 + T cell exhaustion in cancer: What, why and how. Chin J Cancer Res 2024; 36:616-651. [PMID: 39802897 PMCID: PMC11724180 DOI: 10.21147/j.issn.1000-9604.2024.06.04] [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: 09/16/2024] [Accepted: 12/16/2024] [Indexed: 01/16/2025] Open
Abstract
Exhausted T cell (Tex) is a specific state of T cell dysfunction, in which these T cells gradually lose their effector function and change their phenotype during chronic antigen stimulation. The enrichment of exhausted CD8+ T cell (CD8+ Tex) in the tumor microenvironment is one of the important reasons leading to the poor efficacy of immunotherapy. Recent studies have reported many reasons leading to the CD8+ T cell exhaustion. In addition to cancer cells, myeloid cells can also contribute to T cell exhaustion via many ways. In this review, we discuss the history of the concept of exhaustion, CD8+ T cell dysfunction states, the heterogeneity, origin, and characteristics of CD8+ Tex. We then focus on the effects of myeloid cells on CD8+ Tex, including tumor-associated macrophages (TAMs), dendritic cells (DCs) and neutrophils. Finally, we systematically summarize current strategies and recent advancements in therapies reversing and CD8+ T cell exhaustion.
Collapse
Affiliation(s)
- Yijie Zhai
- School of Basic Medical Sciences, Health Science Center, Peking University, Beijing 100191, China
- State Key Laboratory of Molecular Oncology, Peking University International Cancer Institute, Health Science Center, Peking University, Beijing 100191, China
| | - Xiaoting Liang
- School of Basic Medical Sciences, Health Science Center, Peking University, Beijing 100191, China
- State Key Laboratory of Molecular Oncology, Peking University International Cancer Institute, Health Science Center, Peking University, Beijing 100191, China
| | - Mi Deng
- School of Basic Medical Sciences, Health Science Center, Peking University, Beijing 100191, China
- State Key Laboratory of Molecular Oncology, Peking University International Cancer Institute, Health Science Center, Peking University, Beijing 100191, China
- Peking University Cancer Hospital & Institute, Beijing 100142, China
| |
Collapse
|
|
6
|
Zhu Z, Liu H, Fu H, Luo Y, Chen B, Wu X, Sun A, Zhang F, Wang T. CMTM7 shapes the chronic inflammatory and immunosuppressive tumor microenvironment in hepatocellular carcinoma as an M2 macrophage biomarker. Sci Rep 2024; 14:29659. [PMID: 39609464 PMCID: PMC11604762 DOI: 10.1038/s41598-024-75538-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Accepted: 10/07/2024] [Indexed: 11/30/2024] Open
Abstract
Transmembrane domain-containing 7 (CMTM7) is a protein located at the plasma membrane. It plays a role in regulating the development and immune microenvironment of tumor cells. However, the impact of CMTM7 on hepatocellular carcinoma (HCC) is not well understood. To better understand the role of CMTM7 in HCC, the correlations of CMTM7 with clinical characteristics, patient prognosis, chronic inflammation, and immune cell infiltration were analyzed using tissue microarray slides, sequencing datasets and various analysis tools (Web). The bulk sequencing analysis indicated that elevated expression of CMTM7 appears to promote chronic inflammation, immunosuppression, M2 macrophage infiltration, a diminished response to cancer immunotherapy, and an unfavorable clinical prognosis in patients with hepatocellular carcinoma (HCC). Further investigation through single-cell RNA sequencing and multiple fluorescence staining demonstrated that CMTM7 serves as a molecular marker for M2 macrophages and is associated with T cell exhaustion as well as highly plastic stem-like characteristics. We propose that CMTM7 may represent a novel immune checkpoint for HCC patients experiencing suboptimal therapeutic outcomes. Utilizing the Connectivity Map and AutoDock Vina, we predicted two potential compounds targeting CMTM7-fasudil and arachidonyltrifluoromethane-as promising therapeutic candidates. Collectively, these findings suggest that CMTM7-positive macrophages play significant roles in establishing an immunosuppressive tumor microenvironment while promoting highly plastic and stem-like traits in HCC cells, ultimately contributing to poor prognostic outcomes.
Collapse
Affiliation(s)
- Zhipeng Zhu
- Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China
- Department of General Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361103, Fujian, China
| | - Hanzhi Liu
- The Third Clinical Medical College, Gannan Medical University, Ganzhou, 341000, Jiangxi, China
| | - Huafeng Fu
- Center for Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510030, Guangdong, China
| | - Yu Luo
- The Key Laboratory of Urinary Tract Tumors and Calculi, Department of Urology Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, China
| | - Baisheng Chen
- Endoscopy Center, Zhongshan Hospital of Fudan University (Xiamen Branch), Xiamen, 361001, Fujian, China
| | - Xiaofang Wu
- Department of General Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361103, Fujian, China
| | - Anran Sun
- Oncology Research Center, Foresea Life Insurance Guangzhou General Hospital, Guangzhou, 511300, Guangdong, China.
- Research Center for Translational Medicine, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, China.
| | - Fuxing Zhang
- Department of General Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361103, Fujian, China.
| | - Tao Wang
- The Key Laboratory of Urinary Tract Tumors and Calculi, Department of Urology Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, China.
| |
Collapse
|
|
7
|
Wu B, Zhang B, Li B, Wu H, Jiang M. Cold and hot tumors: from molecular mechanisms to targeted therapy. Signal Transduct Target Ther 2024; 9:274. [PMID: 39420203 PMCID: PMC11491057 DOI: 10.1038/s41392-024-01979-x] [Citation(s) in RCA: 60] [Impact Index Per Article: 60.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 08/20/2024] [Accepted: 09/12/2024] [Indexed: 10/19/2024] Open
Abstract
Immunotherapy has made significant strides in cancer treatment, particularly through immune checkpoint blockade (ICB), which has shown notable clinical benefits across various tumor types. Despite the transformative impact of ICB treatment in cancer therapy, only a minority of patients exhibit a positive response to it. In patients with solid tumors, those who respond well to ICB treatment typically demonstrate an active immune profile referred to as the "hot" (immune-inflamed) phenotype. On the other hand, non-responsive patients may exhibit a distinct "cold" (immune-desert) phenotype, differing from the features of "hot" tumors. Additionally, there is a more nuanced "excluded" immune phenotype, positioned between the "cold" and "hot" categories, known as the immune "excluded" type. Effective differentiation between "cold" and "hot" tumors, and understanding tumor intrinsic factors, immune characteristics, TME, and external factors are critical for predicting tumor response and treatment results. It is widely accepted that ICB therapy exerts a more profound effect on "hot" tumors, with limited efficacy against "cold" or "altered" tumors, necessitating combinations with other therapeutic modalities to enhance immune cell infiltration into tumor tissue and convert "cold" or "altered" tumors into "hot" ones. Therefore, aligning with the traits of "cold" and "hot" tumors, this review systematically delineates the respective immune characteristics, influencing factors, and extensively discusses varied treatment approaches and drug targets based on "cold" and "hot" tumors to assess clinical efficacy.
Collapse
Affiliation(s)
- Bo Wu
- Department of Neurology, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Bo Zhang
- Department of Youth League Committee, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Bowen Li
- Department of Pancreatic and Gastrointestinal Surgery, Ningbo No. 2 Hospital, Ningbo, China
| | - Haoqi Wu
- Department of Gynaecology and Obstetrics, The Second Hospital of Dalian Medical University, Dalian, China
| | - Meixi Jiang
- Department of Neurology, The Fourth Affiliated Hospital, China Medical University, Shenyang, China.
| |
Collapse
|
|
8
|
Malik S, Sureka N, Ahuja S, Aden D, Zaheer S, Zaheer S. Tumor-associated macrophages: A sentinel of innate immune system in tumor microenvironment gone haywire. Cell Biol Int 2024; 48:1406-1449. [PMID: 39054741 DOI: 10.1002/cbin.12226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 06/10/2024] [Accepted: 07/08/2024] [Indexed: 07/27/2024]
Abstract
The tumor microenvironment (TME) is a critical determinant in the initiation, progression, and treatment outcomes of various cancers. Comprising of cancer-associated fibroblasts (CAF), immune cells, blood vessels, and signaling molecules, the TME is often likened to the soil supporting the seed (tumor). Among its constituents, tumor-associated macrophages (TAMs) play a pivotal role, exhibiting a dual nature as both promoters and inhibitors of tumor growth. This review explores the intricate relationship between TAMs and the TME, emphasizing their diverse functions, from phagocytosis and tissue repair to modulating immune responses. The plasticity of TAMs is highlighted, showcasing their ability to adopt either protumorigenic or anti-tumorigenic phenotypes based on environmental cues. In the context of cancer, TAMs' pro-tumorigenic activities include promoting angiogenesis, inhibiting immune responses, and fostering metastasis. The manuscript delves into therapeutic strategies targeting TAMs, emphasizing the challenges faced in depleting or inhibiting TAMs due to their multifaceted roles. The focus shifts towards reprogramming TAMs to an anti-tumorigenic M1-like phenotype, exploring interventions such as interferons, immune checkpoint inhibitors, and small molecule modulators. Noteworthy advancements include the use of CSF1R inhibitors, CD40 agonists, and CD47 blockade, demonstrating promising results in preclinical and clinical settings. A significant section is dedicated to Chimeric Antigen Receptor (CAR) technology in macrophages (CAR-M cells). While CAR-T cells have shown success in hematological malignancies, their efficacy in solid tumors has been limited. CAR-M cells, engineered to infiltrate solid tumors, are presented as a potential breakthrough, with a focus on their development, challenges, and promising outcomes. The manuscript concludes with the exploration of third-generation CAR-M technology, offering insight into in-vivo reprogramming and nonviral vector approaches. In conclusion, understanding the complex and dynamic role of TAMs in cancer is crucial for developing effective therapeutic strategies. While early-stage TAM-targeted therapies show promise, further extensive research and larger clinical trials are warranted to optimize their targeting and improve overall cancer treatment outcomes.
Collapse
Affiliation(s)
- Shaivy Malik
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, New Delhi, India
| | - Niti Sureka
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, New Delhi, India
| | - Sana Ahuja
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, New Delhi, India
| | - Durre Aden
- Department of Pathology, Hamdard Institute of Medical Science and Research, Jamia Hamdard, New Delhi, New Delhi, India
| | - Samreen Zaheer
- Department of Radiotherapy, Jawaharlal Nehru Medical College, AMU, Aligarh, India
| | - Sufian Zaheer
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, New Delhi, India
| |
Collapse
|
|
9
|
Muteeb G, Khafaga DS, El-Morsy MT, Farhan M, Aatif M, Hosney M. Targeting tumor-associated macrophages with nanocarrier-based treatment for breast cancer: A step toward developing innovative anti-cancer therapeutics. Heliyon 2024; 10:e37217. [PMID: 39309874 PMCID: PMC11415663 DOI: 10.1016/j.heliyon.2024.e37217] [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: 01/18/2024] [Revised: 08/06/2024] [Accepted: 08/29/2024] [Indexed: 09/25/2024] Open
Abstract
Tumor-associated macrophages (TAMs) promote tumor advancement in many ways, such as inducing angiogenesis and the formation of new blood vessels that provide tumors with nourishment and oxygen. TAMs also facilitate tumor invasion and metastasis by secreting enzymes that degrade the extracellular matrix and generating pro-inflammatory cytokines that enhance the migration of tumor cells. TAMs also have a role in inhibiting the immune response against malignancies. To accomplish this, they release immunosuppressive cytokines such as IL-10, and TAMs can hinder the function of T cells and natural killer cells, which play crucial roles in the immune system's ability to combat cancer. The role of TAMs in breast cancer advancement is a complex and dynamic field of research. Therefore, TAMs are a highly favorable focus for innovative breast cancer treatments. This review presents an extensive overview of the correlation between TAMs and breast cancer development as well as its role in the tumor microenvironment (TME) shedding light on their impact on tumor advancement and immune evasion mechanisms. Notably, our study provides an innovative approach to employing nanomedicine approaches for targeted TAM therapy in breast cancer, providing an in-depth overview of recent advances in this emerging field.
Collapse
Affiliation(s)
- Ghazala Muteeb
- Department of Nursing, College of Applied Medical Sciences, King Faisal University, Al-Ahsa, 31982, Saudi Arabia
| | - Doaa S.R. Khafaga
- Health Sector, Faculty of Science, Galala University, New Galala City, 43511, Suez, Egypt
| | - Manar T. El-Morsy
- Biotechnology Department, Faculty of Science, Cairo University, 12613, Giza, Egypt
| | - Mohd Farhan
- Department of Chemistry, College of Science, King Faisal University, Al Ahsa, 31982, Saudi Arabia
- Department of Basic Sciences, Preparatory Year Deanship, King Faisal University, Al Ahsa, 31982, Saudi Arabia
| | - Mohammad Aatif
- Department of Public Health, College of Applied Medical Sciences, King Faisal University, Al-Ahsa, 31982, Saudi Arabia
| | - Mohamed Hosney
- Zoology Department, Faculty of Science, Cairo University, 12613, Giza, Egypt
| |
Collapse
|
|
10
|
McAndrews KM, Mahadevan KK, Kalluri R. Mouse Models to Evaluate the Functional Role of the Tumor Microenvironment in Cancer Progression and Therapy Responses. Cold Spring Harb Perspect Med 2024; 14:a041411. [PMID: 38191175 PMCID: PMC11216184 DOI: 10.1101/cshperspect.a041411] [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] [Indexed: 01/10/2024]
Abstract
The tumor microenvironment (TME) is a complex ecosystem of both cellular and noncellular components that functions to impact the evolution of cancer. Various aspects of the TME have been targeted for the control of cancer; however, TME composition is dynamic, with the overall abundance of immune cells, endothelial cells (ECs), fibroblasts, and extracellular matrix (ECM) as well as subsets of TME components changing at different stages of progression and in response to therapy. To effectively treat cancer, an understanding of the functional role of the TME is needed. Genetically engineered mouse models have enabled comprehensive insight into the complex interactions within the TME ecosystem that regulate disease progression. Here, we review recent advances in mouse models that have been employed to understand how the TME regulates cancer initiation, progression, metastasis, and response to therapy.
Collapse
Affiliation(s)
- Kathleen M McAndrews
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA
| | - Krishnan K Mahadevan
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA
| | - Raghu Kalluri
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA
- Department of Bioengineering, Rice University, Houston, Texas 77251, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
| |
Collapse
|
|
11
|
Ouyang J, Hu S, Zhu Q, Li C, Kang T, Xie W, Wang Y, Li Y, Lu Y, Qi J, Xia M, Chen J, Yang Y, Sun Y, Gao T, Ye L, Liang Q, Pan Y, Zhu C. RANKL/RANK signaling recruits Tregs via the CCL20-CCR6 pathway and promotes stemness and metastasis in colorectal cancer. Cell Death Dis 2024; 15:437. [PMID: 38902257 PMCID: PMC11190233 DOI: 10.1038/s41419-024-06806-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 05/24/2024] [Accepted: 06/03/2024] [Indexed: 06/22/2024]
Abstract
TNF receptor superfamily member 11a (TNFRSF11a, RANK) and its ligand TNF superfamily member 11 (TNFRSF11, RANKL) are overexpressed in many malignancies. However, the clinical importance of RANKL/RANK in colorectal cancer (CRC) is mainly unknown. We examined CRC samples and found that RANKL/RANK was elevated in CRC tissues compared with nearby normal tissues. A higher RANKL/RANK expression was associated with a worse survival rate. Furthermore, RANKL was mostly produced by regulatory T cells (Tregs), which were able to promote CRC advancement. Overexpression of RANK or addition of RANKL significantly increased the stemness and migration of CRC cells. Furthermore, RANKL/RANK signaling stimulated C-C motif chemokine ligand 20 (CCL20) production by CRC cells, leading to Treg recruitment and boosting tumor stemness and malignant progression. This recruitment process was accomplished by CCL20-CCR6 interaction, demonstrating a connection between CRC cells and immune cells. These findings suggest an important role of RANKL/RANK in CRC progression, offering a potential target for CRC prevention and therapy.
Collapse
Affiliation(s)
- Jing Ouyang
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Shuang Hu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Qingqing Zhu
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Chenxin Li
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Tingting Kang
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Wenlin Xie
- Pathological Diagnostic Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Yun Wang
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Yan Li
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Yingsi Lu
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Junhua Qi
- Department of Clinical Medical Laboratory, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Ming Xia
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Jinrun Chen
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Yingqian Yang
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Yazhou Sun
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
- Clinical Big Data Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Tianshun Gao
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
- Clinical Big Data Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Liping Ye
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China.
| | - Qian Liang
- Department of Spine Surgery, The First Affiliated Hospital of Shenzhen University, The Shenzhen Second People's Hospital, Shenzhen, China.
| | - Yihang Pan
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China.
| | - Chengming Zhu
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China.
| |
Collapse
|
|
12
|
Khosravi G, Mostafavi S, Bastan S, Ebrahimi N, Gharibvand RS, Eskandari N. Immunologic tumor microenvironment modulators for turning cold tumors hot. Cancer Commun (Lond) 2024; 44:521-553. [PMID: 38551889 PMCID: PMC11110955 DOI: 10.1002/cac2.12539] [Citation(s) in RCA: 66] [Impact Index Per Article: 66.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 03/03/2024] [Accepted: 03/12/2024] [Indexed: 05/23/2024] Open
Abstract
Tumors can be classified into distinct immunophenotypes based on the presence and arrangement of cytotoxic immune cells within the tumor microenvironment (TME). Hot tumors, characterized by heightened immune activity and responsiveness to immune checkpoint inhibitors (ICIs), stand in stark contrast to cold tumors, which lack immune infiltration and remain resistant to therapy. To overcome immune evasion mechanisms employed by tumor cells, novel immunologic modulators have emerged, particularly ICIs targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1/programmed death-ligand 1(PD-1/PD-L1). These agents disrupt inhibitory signals and reactivate the immune system, transforming cold tumors into hot ones and promoting effective antitumor responses. However, challenges persist, including primary resistance to immunotherapy, autoimmune side effects, and tumor response heterogeneity. Addressing these challenges requires innovative strategies, deeper mechanistic insights, and a combination of immune interventions to enhance the effectiveness of immunotherapies. In the landscape of cancer medicine, where immune cold tumors represent a formidable hurdle, understanding the TME and harnessing its potential to reprogram the immune response is paramount. This review sheds light on current advancements and future directions in the quest for more effective and safer cancer treatment strategies, offering hope for patients with immune-resistant tumors.
Collapse
Affiliation(s)
- Gholam‐Reza Khosravi
- Department of Medical ImmunologySchool of MedicineIsfahan University of Medical SciencesIsfahanIran
| | - Samaneh Mostafavi
- Department of ImmunologyFaculty of Medical SciencesTarbiat Modares UniversityTehranIran
| | - Sanaz Bastan
- Department of Medical ImmunologySchool of MedicineIsfahan University of Medical SciencesIsfahanIran
| | - Narges Ebrahimi
- Department of Medical ImmunologySchool of MedicineIsfahan University of Medical SciencesIsfahanIran
| | - Roya Safari Gharibvand
- Department of ImmunologySchool of MedicineAhvaz Jundishapur University of Medical SciencesAhvazIran
| | - Nahid Eskandari
- Department of Medical ImmunologySchool of MedicineIsfahan University of Medical SciencesIsfahanIran
| |
Collapse
|
|
13
|
Dakal TC, George N, Xu C, Suravajhala P, Kumar A. Predictive and Prognostic Relevance of Tumor-Infiltrating Immune Cells: Tailoring Personalized Treatments against Different Cancer Types. Cancers (Basel) 2024; 16:1626. [PMID: 38730579 PMCID: PMC11082991 DOI: 10.3390/cancers16091626] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 04/12/2024] [Accepted: 04/17/2024] [Indexed: 05/13/2024] Open
Abstract
TIICs are critical components of the TME and are used to estimate prognostic and treatment responses in many malignancies. TIICs in the tumor microenvironment are assessed and quantified by categorizing immune cells into three subtypes: CD66b+ tumor-associated neutrophils (TANs), FoxP3+ regulatory T cells (Tregs), and CD163+ tumor-associated macrophages (TAMs). In addition, many cancers have tumor-infiltrating M1 and M2 macrophages, neutrophils (Neu), CD4+ T cells (T-helper), CD8+ T cells (T-cytotoxic), eosinophils, and mast cells. A variety of clinical treatments have linked tumor immune cell infiltration (ICI) to immunotherapy receptivity and prognosis. To improve the therapeutic effectiveness of immune-modulating drugs in a wider cancer patient population, immune cells and their interactions in the TME must be better understood. This study examines the clinicopathological effects of TIICs in overcoming tumor-mediated immunosuppression to boost antitumor immune responses and improve cancer prognosis. We successfully analyzed the predictive and prognostic usefulness of TIICs alongside TMB and ICI scores to identify cancer's varied immune landscapes. Traditionally, immune cell infiltration was quantified using flow cytometry, immunohistochemistry, gene set enrichment analysis (GSEA), CIBERSORT, ESTIMATE, and other platforms that use integrated immune gene sets from previously published studies. We have also thoroughly examined traditional limitations and newly created unsupervised clustering and deconvolution techniques (SpatialVizScore and ProTICS). These methods predict patient outcomes and treatment responses better. These models may also identify individuals who may benefit more from adjuvant or neoadjuvant treatment. Overall, we think that the significant contribution of TIICs in cancer will greatly benefit postoperative follow-up, therapy, interventions, and informed choices on customized cancer medicines.
Collapse
Affiliation(s)
- Tikam Chand Dakal
- Genome and Computational Biology Lab, Department of Biotechnology, Mohanlal Sukhadia University, Udaipur 313001, Rajasthan, India
| | - Nancy George
- Department of Biotechnology, Chandigarh University, Mohali 140413, Punjab, India;
| | - Caiming Xu
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of the City of Hope, Monrovia, CA 91010, USA;
| | - Prashanth Suravajhala
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Clappana P.O. 690525, Kerala, India;
| | - Abhishek Kumar
- Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, Karnataka, India
| |
Collapse
|
|
14
|
Yang S, Yang X, Hou Z, Zhu L, Yao Z, Zhang Y, Chen Y, Teng J, Fang C, Chen S, Jia M, Liu Z, Kang S, Chen Y, Li G, Niu Y, Cai Q. Rationale for immune checkpoint inhibitors plus targeted therapy for advanced renal cell carcinoma. Heliyon 2024; 10:e29215. [PMID: 38623200 PMCID: PMC11016731 DOI: 10.1016/j.heliyon.2024.e29215] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 04/02/2024] [Accepted: 04/02/2024] [Indexed: 04/17/2024] Open
Abstract
Renal cell carcinoma (RCC) is a frequent urological malignancy characterized by a high rate of metastasis and lethality. The treatment strategy for advanced RCC has moved through multiple iterations over the past three decades. Initially, cytokine treatment was the only systemic treatment option for patients with RCC. With the development of medicine, antiangiogenic agents targeting vascular endothelial growth factor and mammalian target of rapamycin and immunotherapy, immune checkpoint inhibitors (ICIs) have emerged and received several achievements in the therapeutics of advanced RCC. However, ICIs have still not brought completely satisfactory results due to drug resistance and undesirable side effects. For the past years, the interests form researchers have been attracted by the combination of ICIs and targeted therapy for advanced RCC and the angiogenesis and immunogenic tumor microenvironmental variations in RCC. Therefore, we emphasize the potential principle and the clinical progress of ICIs combined with targeted treatment of advanced RCC, and summarize the future direction.
Collapse
Affiliation(s)
- Siwei Yang
- Department of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Xianrui Yang
- Department of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Zekai Hou
- Department of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Liang Zhu
- Department of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Zhili Yao
- Department of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China
| | | | - Yanzhuo Chen
- Department of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Jie Teng
- Affiliated Hospital of Hebei University, Baoding, China
| | - Cheng Fang
- Taihe County People's Hospital, Anhui, China
| | - Songmao Chen
- Department of Urology, Fujian Provincial Hospital, Fujian, China
- Provincial Clinical Medical College of Fujian Medical University, Fujian, China
| | - Mingfei Jia
- Department of Urology, North China University of Science and Technology Affiliated Hospital, Hebei, China
| | - Zhifei Liu
- Department of Urology, Tangshan People's Hospital, Hebei, China
| | - Shaosan Kang
- Department of Urology, North China University of Science and Technology Affiliated Hospital, Hebei, China
| | - Yegang Chen
- Department of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Gang Li
- Department of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Yuanjie Niu
- Department of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Qiliang Cai
- Department of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China
| |
Collapse
|
|
15
|
Lu C, Liu Y, Miao L, Kong X, Li H, Chen H, Zhao X, Zhang B, Cui X. Research progress on the role of tumor‑associated macrophages in tumor development and their use as molecular targets (Review). Int J Oncol 2024; 64:11. [PMID: 38063203 PMCID: PMC10734668 DOI: 10.3892/ijo.2023.5599] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 11/24/2023] [Indexed: 12/18/2023] Open
Abstract
The tumor microenvironment (TME) is a complex system composed mainly of tumor cells, mesenchymal cells and immune cells. Macrophages, also known as tumor‑associated macrophages (TAMs), among innate immune cells, are some of the most abundant components of the TME. They may influence tumor growth and metastasis through interactions with other cell populations in the TME and have been associated with poor prognosis in a variety of tumors. Therefore, a better understanding of the role of TAMs in the TME may provide new insight into tumor therapy. In the present review, the origin and classification of TAMs in the TME were outlined and their polarization and dual effects on tumor cells, as well as emerging strategies for cancer therapies targeting TAMs, were discussed.
Collapse
Affiliation(s)
- Chenglin Lu
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 860411, P.R. China
| | - Ying Liu
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 860411, P.R. China
- Department of Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 860411, P.R. China
| | - Linxuan Miao
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 860411, P.R. China
| | - Xiangle Kong
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 860411, P.R. China
| | - Huili Li
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 860411, P.R. China
| | - Haoran Chen
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 860411, P.R. China
| | - Xu Zhao
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 860411, P.R. China
| | - Bin Zhang
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 860411, P.R. China
| | - Xiaonan Cui
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 860411, P.R. China
| |
Collapse
|
|
16
|
Hou S, Zhao Y, Chen J, Lin Y, Qi X. Tumor-associated macrophages in colorectal cancer metastasis: molecular insights and translational perspectives. J Transl Med 2024; 22:62. [PMID: 38229160 PMCID: PMC10792812 DOI: 10.1186/s12967-024-04856-x] [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: 08/11/2023] [Accepted: 01/03/2024] [Indexed: 01/18/2024] Open
Abstract
Metastasis is the leading cause of high mortality in colorectal cancer (CRC), which is not only driven by changes occurring within the tumor cells, but is also influenced by the dynamic interaction between cancer cells and components in the tumor microenvironment (TME). Currently, the exploration of TME remodeling and its impact on CRC metastasis has attracted increasing attention owing to its potential to uncover novel therapeutic avenues. Noteworthy, emerging studies suggested that tumor-associated macrophages (TAMs) within the TME played important roles in CRC metastasis by secreting a variety of cytokines, chemokines, growth factors and proteases. Moreover, TAMs are often associated with poor prognosis and drug resistance, making them promising targets for CRC therapy. Given the prognostic and clinical value of TAMs, this review provides an updated overview on the origin, polarization and function of TAMs, and discusses the mechanisms by which TAMs promote the metastatic cascade of CRC. Potential TAM-targeting techniques for personalized theranostics of metastatic CRC are emphasized. Finally, future perspectives and challenges for translational applications of TAMs in CRC development and metastasis are proposed to help develop novel TAM-based strategies for CRC precision medicine and holistic healthcare.
Collapse
Affiliation(s)
- Siyu Hou
- School of Chemistry and Life Sciences, Suzhou University of Science and Technology, Suzhou, 215011, China
| | - Yuanchun Zhao
- School of Chemistry and Life Sciences, Suzhou University of Science and Technology, Suzhou, 215011, China
| | - Jiajia Chen
- School of Chemistry and Life Sciences, Suzhou University of Science and Technology, Suzhou, 215011, China
| | - Yuxin Lin
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, 215000, China.
- Center for Systems Biology, Department of Bioinformatics, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, 215123, China.
| | - Xin Qi
- School of Chemistry and Life Sciences, Suzhou University of Science and Technology, Suzhou, 215011, China.
| |
Collapse
|
|
17
|
Arroyo-Olarte R, Mejía-Muñoz A, León-Cabrera S. Expanded Alternatives of CRISPR-Cas9 Applications in Immunotherapy of Colorectal Cancer. Mol Diagn Ther 2024; 28:69-86. [PMID: 37907826 PMCID: PMC10786962 DOI: 10.1007/s40291-023-00680-z] [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] [Accepted: 10/04/2023] [Indexed: 11/02/2023]
Abstract
Immunotherapy for colorectal cancer (CRC) is limited to patients with advanced disease who have already undergone first-line chemotherapy and whose tumors exhibit microsatellite instability. Novel technical strategies are required to enhance therapeutic options and achieve a more robust immunological response. Therefore, exploring gene analysis and manipulation at the molecular level can further accelerate the development of advanced technologies to address these challenges. The emergence of advanced genome editing technology, particularly of clustered, regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas) 9, holds promise in expanding the boundaries of cancer immunotherapy. In this manuscript, we provide a comprehensive review of the applications and perspectives of CRISPR technology in improving the design, generation, and efficiency of current immunotherapies, focusing on solid tumors such as colorectal cancer, where these approaches have not been as successful as in hematological conditions.
Collapse
Affiliation(s)
- Rubén Arroyo-Olarte
- Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Los Reyes Iztacala, 54090, Tlalnepantla, Edo. De México, México
- Carrera de Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, 54090, Tlalnepantla, Edo. De México, México
| | - Aranza Mejía-Muñoz
- Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Los Reyes Iztacala, 54090, Tlalnepantla, Edo. De México, México
- Carrera de Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, 54090, Tlalnepantla, Edo. De México, México
| | - Sonia León-Cabrera
- Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Los Reyes Iztacala, 54090, Tlalnepantla, Edo. De México, México.
- Carrera de Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, 54090, Tlalnepantla, Edo. De México, México.
| |
Collapse
|
|
18
|
Benešová I, Křížová Ľ, Kverka M. Microbiota as the unifying factor behind the hallmarks of cancer. J Cancer Res Clin Oncol 2023; 149:14429-14450. [PMID: 37555952 PMCID: PMC10590318 DOI: 10.1007/s00432-023-05244-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 08/01/2023] [Indexed: 08/10/2023]
Abstract
The human microbiota is a complex ecosystem that colonizes body surfaces and interacts with host organ systems, especially the immune system. Since the composition of this ecosystem depends on a variety of internal and external factors, each individual harbors a unique set of microbes. These differences in microbiota composition make individuals either more or less susceptible to various diseases, including cancer. Specific microbes are associated with cancer etiology and pathogenesis and several mechanisms of how they drive the typical hallmarks of cancer were recently identified. Although most microbes reside in the distal gut, they can influence cancer initiation and progression in distant tissues, as well as modulate the outcomes of established cancer therapies. Here, we describe the mechanisms by which microbes influence carcinogenesis and discuss their current and potential future applications in cancer diagnostics and management.
Collapse
Affiliation(s)
- Iva Benešová
- Laboratory of Cellular and Molecular Immunology, Institute of Microbiology v.v.i., Czech Academy of Sciences, Vídeňská 1083, 142 00, Prague 4-Krč, Czech Republic
| | - Ľudmila Křížová
- Department of Oncology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic
| | - Miloslav Kverka
- Laboratory of Cellular and Molecular Immunology, Institute of Microbiology v.v.i., Czech Academy of Sciences, Vídeňská 1083, 142 00, Prague 4-Krč, Czech Republic.
| |
Collapse
|
|
19
|
Sun Y, Jiang G, Wu Q, Ye L, Li B. The role of tumor-associated macrophages in the progression, prognosis and treatment of endometrial cancer. Front Oncol 2023; 13:1213347. [PMID: 37810971 PMCID: PMC10556650 DOI: 10.3389/fonc.2023.1213347] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 08/18/2023] [Indexed: 10/10/2023] Open
Abstract
Tumor-associated macrophages (TAMs) are the main immune cells in the tumor microenvironment (TME) of endometrial cancer (EC). TAMs recruitment and polarization in EC is regulated by the TME of EC, culminating in a predominantly M2-like macrophage infiltration. TAMs promote lymphatic angiogenesis through cytokine secretion, aid immune escape of EC cells by synergizing with other immune cells, and contribute to the development of EC through secretion of exosomes so as to promoting EC development. EC is a hormone- and metabolism-dependent cancer, and TAMs promote EC through interactions on estrogen receptor (ER) and metabolic factors such as the metabolism of glucose, lipids, and amino acids. In addition, we have explored the predictive significance of some TAM-related indicators for EC prognosis, and TAMs show remarkable promise as a target for EC immunotherapy.
Collapse
Affiliation(s)
- Yihan Sun
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Genyi Jiang
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Qianhua Wu
- School of Medicine, Tongji University, Shanghai, China
| | - Lei Ye
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Bilan Li
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| |
Collapse
|
|
20
|
Shakhpazyan N, Mikhaleva L, Bedzhanyan A, Gioeva Z, Sadykhov N, Mikhalev A, Atiakshin D, Buchwalow I, Tiemann M, Orekhov A. Cellular and Molecular Mechanisms of the Tumor Stroma in Colorectal Cancer: Insights into Disease Progression and Therapeutic Targets. Biomedicines 2023; 11:2361. [PMID: 37760801 PMCID: PMC10525158 DOI: 10.3390/biomedicines11092361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 07/31/2023] [Accepted: 08/21/2023] [Indexed: 09/29/2023] Open
Abstract
Colorectal cancer (CRC) is a major health burden worldwide and is the third most common type of cancer. The early detection and diagnosis of CRC is critical to improve patient outcomes. This review explores the intricate interplay between the tumor microenvironment, stromal interactions, and the progression and metastasis of colorectal cancer. The review begins by assessing the gut microbiome's influence on CRC development, emphasizing its association with gut-associated lymphoid tissue (GALT). The role of the Wnt signaling pathway in CRC tumor stroma is scrutinized, elucidating its impact on disease progression. Tumor budding, its effect on tumor stroma, and the implications for patient prognosis are investigated. The review also identifies conserved oncogenic signatures (COS) within CRC stroma and explores their potential as therapeutic targets. Lastly, the seed and soil hypothesis is employed to contextualize metastasis, accentuating the significance of both tumor cells and the surrounding stroma in metastatic propensity. This review highlights the intricate interdependence between CRC cells and their microenvironment, providing valuable insights into prospective therapeutic approaches targeting tumor-stroma interactions.
Collapse
Affiliation(s)
- Nikolay Shakhpazyan
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Center of Surgery, 119435 Moscow, Russia; (N.S.); (L.M.); (Z.G.); (N.S.); (A.O.)
| | - Liudmila Mikhaleva
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Center of Surgery, 119435 Moscow, Russia; (N.S.); (L.M.); (Z.G.); (N.S.); (A.O.)
| | - Arkady Bedzhanyan
- Department of Abdominal Surgery and Oncology II (Coloproctology and Uro-Gynecology), Petrovsky National Research Center of Surgery, 119435 Moscow, Russia;
| | - Zarina Gioeva
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Center of Surgery, 119435 Moscow, Russia; (N.S.); (L.M.); (Z.G.); (N.S.); (A.O.)
| | - Nikolay Sadykhov
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Center of Surgery, 119435 Moscow, Russia; (N.S.); (L.M.); (Z.G.); (N.S.); (A.O.)
| | - Alexander Mikhalev
- Department of Hospital Surgery No. 2, Pirogov Russian National Research Medical University, 117997 Moscow, Russia;
| | - Dmitri Atiakshin
- Research and Educational Resource Center for Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis Innovative Technologies, Peoples’ Friendship University of Russia, 117198 Moscow, Russia;
- Research Institute of Experimental Biology and Medicine, Burdenko Voronezh State Medical University, 394036 Voronezh, Russia
| | - Igor Buchwalow
- Research and Educational Resource Center for Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis Innovative Technologies, Peoples’ Friendship University of Russia, 117198 Moscow, Russia;
- Institute for Hematopathology, 22547 Hamburg, Germany;
| | | | - Alexander Orekhov
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Center of Surgery, 119435 Moscow, Russia; (N.S.); (L.M.); (Z.G.); (N.S.); (A.O.)
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia
- Institute for Atherosclerosis Research, 121096 Moscow, Russia
| |
Collapse
|
|
21
|
Wróblewska A, Szczygieł A, Szermer-Olearnik B, Pajtasz-Piasecka E. Macrophages as Promising Carriers for Nanoparticle Delivery in Anticancer Therapy. Int J Nanomedicine 2023; 18:4521-4539. [PMID: 37576466 PMCID: PMC10422973 DOI: 10.2147/ijn.s421173] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 07/19/2023] [Indexed: 08/15/2023] Open
Abstract
Macrophages play a critical role in the immune response due to their ability to recognize and remove pathogens, as well as present antigens, which are involved in inflammation, but they are also one of the most abundant immune cell populations present in the tumor microenvironment. In recent years, macrophages have become promising cellular carriers for drug and nanoparticle delivery to the tumor microenvironment, mainly due to their natural properties such as biocompatibility, degradability, lack of immunogenicity, long half-life in circulation, crossing biological barriers, and the possibility of migration and accumulation at a site of inflammation such as a tumor. For the effectiveness of this therapeutic strategy, known as "Trojan horse", it is important that the nanoparticles engulfed by macrophages do not affect their proper functioning. In our review, we discussed how the size, shape, chemical and mechanical properties of nanoparticles influence their internalization by macrophages. In addition, we described the promising research utilizing macrophages, their cell membranes and macrophage-derived exosomes as drug carriers in anticancer therapy. As a prospect of the wider use of this therapeutic strategy, we postulate its future application in boron delivery to the tumor environment in boron neutron capture therapy.
Collapse
Affiliation(s)
- Anna Wróblewska
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Agnieszka Szczygieł
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Bożena Szermer-Olearnik
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Elżbieta Pajtasz-Piasecka
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| |
Collapse
|
|
22
|
Korotkaja K, Jansons J, Spunde K, Rudevica Z, Zajakina A. Establishment and Characterization of Free-Floating 3D Macrophage Programming Model in the Presence of Cancer Cell Spheroids. Int J Mol Sci 2023; 24:10763. [PMID: 37445941 DOI: 10.3390/ijms241310763] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 06/22/2023] [Accepted: 06/23/2023] [Indexed: 07/15/2023] Open
Abstract
Reprogramming of tumor-associated macrophages (TAMs) is a promising strategy for cancer immunotherapy. Several studies have shown that cancer cells induce/support the formation of immunosuppressive TAMs phenotypes. However, the specific factors that orchestrate this immunosuppressive process are unknown or poorly studied. In vivo studies are expensive, complex, and ethically constrained. Therefore, 3D cell interaction models could become a unique framework for the identification of important TAMs programming factors. In this study, we have established and characterized a new in vitro 3D model for macrophage programming in the presence of cancer cell spheroids. First, it was demonstrated that the profile of cytokines, chemokines, and surface markers of 3D-cultured macrophages did not differ conceptually from monolayer-cultured M1 and M2-programmed macrophages. Second, the possibility of reprogramming macrophages in 3D conditions was investigated. In total, the dynamic changes in 6 surface markers, 11 cytokines, and 22 chemokines were analyzed upon macrophage programming (M1 and M2) and reprogramming (M1→M2 and M2→M1). According to the findings, the reprogramming resulted in a mixed macrophage phenotype that expressed both immunosuppressive and anti-cancer immunostimulatory features. Third, cancer cell spheroids were shown to stimulate the production of immunosuppressive M2 markers as well as pro-tumor cytokines and chemokines. In summary, the newly developed 3D model of cancer cell spheroid/macrophage co-culture under free-floating conditions can be used for studies on macrophage plasticity and for the development of targeted cancer immunotherapy.
Collapse
Affiliation(s)
- Ksenija Korotkaja
- Cancer Gene Therapy Group, Latvian Biomedical Research and Study Centre, Ratsupites Str. 1, k.1, LV-1067 Riga, Latvia
| | - Juris Jansons
- Cancer Gene Therapy Group, Latvian Biomedical Research and Study Centre, Ratsupites Str. 1, k.1, LV-1067 Riga, Latvia
| | - Karina Spunde
- Cancer Gene Therapy Group, Latvian Biomedical Research and Study Centre, Ratsupites Str. 1, k.1, LV-1067 Riga, Latvia
| | - Zhanna Rudevica
- Cancer Gene Therapy Group, Latvian Biomedical Research and Study Centre, Ratsupites Str. 1, k.1, LV-1067 Riga, Latvia
| | - Anna Zajakina
- Cancer Gene Therapy Group, Latvian Biomedical Research and Study Centre, Ratsupites Str. 1, k.1, LV-1067 Riga, Latvia
| |
Collapse
|
|
23
|
Zhang H, Liu L, Liu J, Dang P, Hu S, Yuan W, Sun Z, Liu Y, Wang C. Roles of tumor-associated macrophages in anti-PD-1/PD-L1 immunotherapy for solid cancers. Mol Cancer 2023; 22:58. [PMID: 36941614 PMCID: PMC10029244 DOI: 10.1186/s12943-023-01725-x] [Citation(s) in RCA: 167] [Impact Index Per Article: 83.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 01/16/2023] [Indexed: 03/23/2023] Open
Abstract
In recent years, tumor immunotherapy has made significant progress. However, tumor immunotherapy, particularly immune checkpoint inhibitors (e.g., PD-1/PD-L1 inhibitors), benefits only a tiny proportion of patients in solid cancers. The tumor microenvironment (TME) acts a significant role in tumor immunotherapy. Studies reported that tumor-associated macrophages (TAMs), as one of the main components of TME, seriously affected the therapeutic effect of PD-1/PD-L1 inhibitors. In this review, we analyzed TAMs from epigenetic and single-cell perspectives and introduced the role and mechanisms of TAMs in anti-programmed death protein 1(anti-PD-1) therapy. In addition, we summarized combination regimens that enhance the efficacy of tumor PD-1/PD-L1 inhibitors and elaborated on the role of the TAMs in different solid cancers. Eventually, the clinical value of TAMs by influencing the therapeutic effect of tumor PD-1/PD-L1 inhibitors was discussed. These above are beneficial to elucidate poor therapeutic effect of PD-1/PD-L1 inhibitors in solid tumors from the point of view of TAMs and explore the strategies to improve its objective remission rate of solid cancers.
Collapse
Affiliation(s)
- Hao Zhang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450001, China
| | - Lin Liu
- Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
- Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Jinbo Liu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450001, China
| | - Pengyuan Dang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450001, China
| | - Shengyun Hu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450001, China
| | - Weitang Yuan
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450001, China
| | - Zhenqiang Sun
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450001, China.
- Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Yang Liu
- Department of Radiotherapy, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450001, China.
| | - Chengzeng Wang
- Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
- Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
| |
Collapse
|
|
24
|
Yu J, Lai M, Zhou Z, Zhou J, Hu Q, Li J, Li H, Chen L, Wen L, Zhou M, Cai L. The PTEN-associated immune prognostic signature reveals the landscape of the tumor microenvironment in glioblastoma. J Neuroimmunol 2023; 376:578034. [PMID: 36791582 DOI: 10.1016/j.jneuroim.2023.578034] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/11/2023] [Accepted: 01/22/2023] [Indexed: 01/26/2023]
Abstract
Glioblastoma (GBM) is a common brain tumor with a complex and diverse tumor microenvironment (TME). As PTEN mutation is the most common mutation in GBM, we aimed to investigate how PTEN mutation regulates the immune response in GBM TME and thus affects the prognosis of GBM patients. In this study, we conducted a comprehensive analysis of multiple levels of data, including whole-exome sequencing (WES), transcriptome RNA sequencing, patient survival and immune signatures, to study the relationship between PTEN mutation and TME in GBM. We developed an immune-related prognostic signature (IPS) based on the PTEN-associated immune-related genes (IRGs), and the IPS exhibited a powerful prognosis prediction capacity in different GBM cohorts. A scoring nomogram based on the IPS was also established for clinical application. In addition, the correlations of the IPS with tumor immune cell infiltration and immune checkpoints were systematically analyzed. This study illustrates the influence of PTEN mutation on the immune microenvironment of GBM. Our IPS, which is sensitive to PTEN mutation status, can enhance the prognosis prediction ability for GBM patients and provides potential targets for immunotherapy.
Collapse
Affiliation(s)
- Jiayin Yu
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Mingyao Lai
- Department of Oncology, Guangdong Sanjiu Brain Hospital, Guangzhou 510510, China
| | - Zhaoming Zhou
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China; Department of Oncology, Guangdong Sanjiu Brain Hospital, Guangzhou 510510, China.
| | - Jiangfen Zhou
- Department of Oncology, Guangdong Sanjiu Brain Hospital, Guangzhou 510510, China
| | - Qingjun Hu
- Department of Oncology, Guangdong Sanjiu Brain Hospital, Guangzhou 510510, China
| | - Juan Li
- Department of Oncology, Guangdong Sanjiu Brain Hospital, Guangzhou 510510, China
| | - Hainan Li
- Department of Pathology, Guangdong Sanjiu Brain Hospital, Guangzhou 510510, China
| | - Longhua Chen
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Lei Wen
- Department of Oncology, Guangdong Sanjiu Brain Hospital, Guangzhou 510510, China
| | - Meijuan Zhou
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China.
| | - Linbo Cai
- Department of Oncology, Guangdong Sanjiu Brain Hospital, Guangzhou 510510, China.
| |
Collapse
|
|
25
|
Zhang R, Dong M, Tu J, Li F, Deng Q, Xu J, He X, Ding J, Xia J, Sheng D, Chang Z, Ma W, Dong H, Zhang Y, Zhang L, Zhang L, Liu S. PMN-MDSCs modulated by CCL20 from cancer cells promoted breast cancer cell stemness through CXCL2-CXCR2 pathway. Signal Transduct Target Ther 2023; 8:97. [PMID: 36859354 PMCID: PMC9977784 DOI: 10.1038/s41392-023-01337-3] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 01/05/2023] [Accepted: 01/29/2023] [Indexed: 03/03/2023] Open
Abstract
Our previous studies have showed that C-C motif chemokine ligand 20 (CCL20) advanced tumor progression and enhanced the chemoresistance of cancer cells by positively regulating breast cancer stem cell (BCSC) self-renewal. However, it is unclear whether CCL20 affects breast cancer progression by remodeling the tumor microenvironment (TME). Here, we observed that polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were remarkably enriched in TME of CCL20-overexpressing cancer cell orthotopic allograft tumors. Mechanistically, CCL20 activated the differentiation of granulocyte-monocyte progenitors (GMPs) via its receptor C-C motif chemokine receptor 6 (CCR6) leading to the PMN-MDSC expansion. PMN-MDSCs from CCL20-overexpressing cell orthotopic allograft tumors (CCL20-modulated PMN-MDSCs) secreted amounts of C-X-C motif chemokine ligand 2 (CXCL2) and increased ALDH+ BCSCs via activating CXCR2/NOTCH1/HEY1 signaling pathway. Furthermore, C-X-C motif chemokine receptor 2 (CXCR2) antagonist SB225002 enhanced the docetaxel (DTX) effects on tumor growth by decreasing BCSCs in CCL20high-expressing tumors. These findings elucidated how CCL20 modulated the TME to promote cancer development, indicating a new therapeutic strategy by interfering with the interaction between PMN-MDSCs and BCSCs in breast cancer, especially in CCL20high-expressing breast cancer.
Collapse
Affiliation(s)
- Rui Zhang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai, 200032, China
| | - Mengxue Dong
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai, 200032, China
| | - Juchuanli Tu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai, 200032, China
| | - Fengkai Li
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai, 200032, China
| | - Qiaodan Deng
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai, 200032, China
| | - Jiahui Xu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai, 200032, China
| | - Xueyan He
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai, 200032, China
| | - Jiajun Ding
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai, 200032, China
- Breast Surgery, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Jie Xia
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai, 200032, China
| | - Dandan Sheng
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai, 200032, China
| | - Zhaoxia Chang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai, 200032, China
| | - Wei Ma
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai, 200032, China
| | - Haonan Dong
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai, 200032, China
| | - Yi Zhang
- Department of Breast and Thyroid Surgery, Southwest Hospital, the First Affiliated Hospital of the Army Military Medical University, Chongqing, 400038, China
| | - Lixing Zhang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai, 200032, China
| | - Lu Zhang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai, 200032, China.
| | - Suling Liu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai, 200032, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, 211166, China.
| |
Collapse
|
|
26
|
Cheruku S, Rao V, Pandey R, Rao Chamallamudi M, Velayutham R, Kumar N. Tumor-associated macrophages employ immunoediting mechanisms in colorectal tumor progression: Current research in Macrophage repolarization immunotherapy. Int Immunopharmacol 2023; 116:109569. [PMID: 36773572 DOI: 10.1016/j.intimp.2022.109569] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 12/01/2022] [Accepted: 12/07/2022] [Indexed: 02/11/2023]
Abstract
Tumor-associated macrophages (TAMs) constitute the most prolific resident of the tumor microenvironment (TME) that regulate its TME into tumor suppressive or progressive milieu by utilizing immunoediting machinery. Here, the tumor cells construct an immunosuppressive microenvironment that educates TAMs to polarize from anti-tumor TAM-M1 to pro-tumor TAM-M2 phenotype consequently contributing to tumor progression. In colorectal cancer (CRC), the TME displays a prominent pro-tumorigenic immune profile with elevated expression of immune-checkpoint molecules notably PD-1, CTLA4, etc., in both MSI and ultra-mutated MSS tumors. This authenticated immune-checkpoint inhibition (ICI) immunotherapy as a pre-requisite for clinical benefit in CRC. However, in response to ICI, specifically, the MSIhi tumors evolved to produce novel immune escape variants thus undermining ICI. Lately, TAM-directed therapies extending from macrophage depletion to repolarization have enabled TME alteration. While TAM accrual implicates clinical benefit in CRC, sustained inflammatory insult may program TAMs to shift from M1 to M2 phenotype. Their ability to oscillate on both facets of the spectrum represents macrophage repolarization immunotherapy as an effective approach to treating CRC. In this review, we briefly discuss the differentiation heterogeneity of colonic macrophages that partake in macrophage-directed immunoediting mechanisms in CRC progression and its employment in macrophage re-polarization immunotherapy.
Collapse
Affiliation(s)
- SriPragnya Cheruku
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal- 576104, Karnataka, India
| | - Vanishree Rao
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal- 576104, Karnataka, India
| | - Ruchi Pandey
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education, and Research, Hajipur, Export Promotions Industrial Park (EPIP), Industrial area, Hajipur, Vaishali, 844102, Bihar, India
| | - Mallikarjuna Rao Chamallamudi
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal- 576104, Karnataka, India
| | - Ravichandiran Velayutham
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education, and Research, Hajipur, Export Promotions Industrial Park (EPIP), Industrial area, Hajipur, Vaishali, 844102, Bihar, India
| | - Nitesh Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education, and Research, Hajipur, Export Promotions Industrial Park (EPIP), Industrial area, Hajipur, Vaishali, 844102, Bihar, India.
| |
Collapse
|
|
27
|
Kazakova A, Sudarskikh T, Kovalev O, Kzhyshkowska J, Larionova I. Interaction of tumor‑associated macrophages with stromal and immune components in solid tumors: Research progress (Review). Int J Oncol 2023; 62:32. [PMID: 36660926 PMCID: PMC9851132 DOI: 10.3892/ijo.2023.5480] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 12/07/2022] [Indexed: 01/18/2023] Open
Abstract
Tumor‑associated macrophages (TAMs) are crucial cells of the tumor microenvironment (TME), which belong to the innate immune system and regulate primary tumor growth, immunosuppression, angiogenesis, extracellular matrix remodeling and metastasis. The review discusses current knowledge of essential cell‑cell interactions of TAMs within the TME of solid tumors. It summarizes the mechanisms of stromal cell (including cancer‑associated fibroblasts and endothelial cells)‑mediated monocyte recruitment and regulation of differentiation, as well as pro‑tumor and antitumor polarization of TAMs. Additionally, it focuses on the perivascular TAM subpopulations that regulate angiogenesis and lymphangiogenesis. It describes the possible mechanisms of reciprocal interactions of TAMs with other immune cells responsible for immunosuppression. Finally, it highlights the perspectives for novel therapeutic approaches to use combined cellular targets that include TAMs and other stromal and immune cells in the TME. The collected data demonstrated the importance of understanding cell‑cell interactions in the TME to prevent distant metastasis and reduce the risk of tumor recurrence.
Collapse
Affiliation(s)
- Anna Kazakova
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk 634050, Russian Federation
| | - Tatiana Sudarskikh
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk 634050, Russian Federation
| | - Oleg Kovalev
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634009, Russian Federation
| | - Julia Kzhyshkowska
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk 634050, Russian Federation
- Institute of Transfusion Medicine and Immunology, Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, D-68167 Mannheim, Germany
| | - Irina Larionova
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk 634050, Russian Federation
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634009, Russian Federation
| |
Collapse
|
|
28
|
Atreya I, Neurath MF. How the Tumor Micromilieu Modulates the Recruitment and Activation of Colorectal Cancer-Infiltrating Lymphocytes. Biomedicines 2022; 10:biomedicines10112940. [PMID: 36428508 PMCID: PMC9687992 DOI: 10.3390/biomedicines10112940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 11/10/2022] [Accepted: 11/11/2022] [Indexed: 11/17/2022] Open
Abstract
The successful treatment of advanced colorectal cancer disease still represents an insufficiently solved clinical challenge, which is further complicated by the fact that the majority of malignant colon tumors show only relatively low immunogenicity and therefore have only limited responsiveness to immunotherapeutic approaches, such as, for instance, the use of checkpoint inhibitors. As it has been well established over the past two decades that the local tumor microenvironment and, in particular, the quantity, quality, and activation status of intratumoral immune cells critically influence the clinical prognosis of patients diagnosed with colorectal cancer and their individual benefits from immunotherapy, the enhancement of the intratumoral accumulation of cytolytic effector T lymphocytes and other cellular mediators of the antitumor immune response has emerged as a targeted objective. For the future identification and clinical validation of novel therapeutic target structures, it will thus be essential to further decipher the molecular mechanisms and cellular interactions in the intestinal tumor microenvironment, which are crucially involved in immune cell recruitment and activation. In this context, our review article aims at providing an overview of the key chemokines and cytokines whose presence in the tumor micromilieu relevantly modulates the numeric composition and antitumor capacity of tumor-infiltrating lymphocytes.
Collapse
Affiliation(s)
- Imke Atreya
- Department of Medicine 1, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Markus F. Neurath
- Department of Medicine 1, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Correspondence: ; Tel.: +49-9131-8535204; Fax: +49-9131-8535209
| |
Collapse
|
|
29
|
PA-MSHA induces inflamed tumor microenvironment and sensitizes tumor to anti-PD-1 therapy. Cell Death Dis 2022; 13:931. [PMID: 36344505 PMCID: PMC9640707 DOI: 10.1038/s41419-022-05368-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 07/08/2022] [Accepted: 10/21/2022] [Indexed: 11/09/2022]
Abstract
A low response rate to immune checkpoint inhibitor (ICI) therapy has impeded its clinical use. As reported previously, an inflamed tumor microenvironment (TME) was directly correlated with patients' response to immune checkpoint blockade (ICB). Thus, restoring the cytotoxic effect of immune cells in the TME is a promising way to improve the efficacy of ICB and overcome primary resistance to immunotherapy. The effect of Pseudomonas aeruginosa mannose-sensitive-hemagglutinin (PA-MSHA) in facilitating T cell activation was determined in vitro and in vivo. Subsets of immune cells were analyzed by flow cytometry. Proteomics was carried out to comprehensively analyze the discriminated cellular kinases and transcription factors. The combinational efficacy of PA-MSHA and αPD-1 therapy was studied in vivo. In this study we demonstrated that PA-MSHA, which is a clinically used immune adjuvant, effectively induced the anti-tumor immune response and suppressed the growth of non-small cell lung cancer (NSCLC) cells. PA-MSHA showed great potential to sensitize refractory "cold" tumors to immunotherapy. It effectively enhanced macrophage M1 polarization and induced T cell activation. In vivo, in combination with αPD-1, PA-MSHA suppressed tumor growth and prolonged the survival time of allograft model mice. These results indicate that PA-MSHA is a potent agent to stimulate immune cells infiltration into the TME and consequently induces inflammation in tumors. The combination of PA-MSHA with αPD-1 is a potential strategy to enhance the clinical response rate to ICI therapy.
Collapse
|
|
30
|
Shen X, Zhou S, Yang Y, Hong T, Xiang Z, Zhao J, Zhu C, Zeng L, Zhang L. TAM-targeted reeducation for enhanced cancer immunotherapy: Mechanism and recent progress. Front Oncol 2022; 12:1034842. [PMID: 36419877 PMCID: PMC9677115 DOI: 10.3389/fonc.2022.1034842] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 10/10/2022] [Indexed: 11/09/2022] Open
Abstract
Tumor-associated macrophage (TAM) as an important component of tumor microenvironment (TME) are closely related with the occurrence, development, and metastasis of malignant tumors. TAMs are generally identified as two distinct functional populations in TME, i.e., inflammatory/anti-tumorigenic (M1) and regenerative/pro-tumorigenic (M2) phenotype. Evidence suggests that occupation of the TME by M2-TAMs is closely related to the inactivation of anti-tumor immune cells such as T cells in TME. Recently, efforts have been made to reeducate TAMs from M2- to M1- phenotype to enhance cancer immunotherapy, and great progress has been made in realizing efficient modulation of TAMs using nanomedicines. To help readers better understand this emerging field, the potential TAM reeducation targets for potentiating cancer immunotherapy and the underlying mechanisms are summarized in this review. Moreover, the most recent advances in utilizing nanomedicine for the TAM immunomodulation for augmented cancer immunotherapy are introduced. Finally, we conclude with our perspectives on the future development in this field.
Collapse
Affiliation(s)
- Xinyuan Shen
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Zhejiang University City College, Hangzhou, China
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Shengcheng Zhou
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yidong Yang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Tu Hong
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Ze Xiang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Jing Zhao
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Chaojie Zhu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Linghui Zeng
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Zhejiang University City College, Hangzhou, China
| | - Lingxiao Zhang
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Zhejiang University City College, Hangzhou, China
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Ningbo Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China
| |
Collapse
|
|
31
|
Ma K, Sun Z, Li X, Guo J, Wang Q, Teng M. Forkhead box M1 recruits FoxP3 + Treg cells to induce immune escape in hilar cholangiocarcinoma. Immun Inflamm Dis 2022; 10:e727. [PMID: 36301031 PMCID: PMC9597491 DOI: 10.1002/iid3.727] [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] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/31/2022] [Accepted: 09/13/2022] [Indexed: 11/06/2022] Open
Abstract
OBJECTIVE Hilar cholangiocarcinoma (HCCA) is a malignancy related to chronic biliary tract inflammation. Tumor immune escape is a necessary process of tumorigenesis. Forkhead box M1 (FoxM1) could affect the progression of various carcinomas. This study attempted to elaborate on the mechanism of FoxM1 in HCCA immune escape. METHODS HCCA cell lines were collected to measure the expression of FoxM1 and FoxP3. CD8+ T cells were extracted to establish the co-culture system with HCCA cells and Treg cells. pcDNA3.1-FoxM1 or si-FoxP3 was transfected into HCCA cells in the co-culture system. HCCA cell viability, mobility, and invasiveness as well as levels of transforming growth factor (TGF)-β and interleukin (IL)-6 were evaluated. The binding relation between FoxM1 and FoxP3 promoter was verified. HCCA cells with pcDNA3.1-FoxM1 were subcutaneously injected into mice to establish the xenograft mouse models. RESULTS FoxM1 and FoxP3 were overexpressed in HCCA cells. The co-culture of CD8+ T and HCCA cells inhibited HCCA cell activity and Treg cells limited CD8+ T killing. FoxM1 overexpression strengthened the inhibiting role of Treg cells in CD8+ T killing, upregulated TGF-β and IL-6 levels, and encouraged HCCA immune escape. FoxM1 bound to the FoxP3 promoter region to promote FoxP3 transcription. Silencing of FoxP3 neutralized the promoting role of FoxM1 overexpression in Treg cell immunosuppression and HCCA cell immune escape. FoxM1 aggravated tumor development, upregulated FoxP3 expression, increased Treg cells, and reduced CD8+ T cells. CONCLUSION FoxM1 bound to the FoxP3 promoter region to promote FoxP3 transcription and recruited FoxP3+ Treg cells, thereby inducing HCCA immune escape.
Collapse
Affiliation(s)
- Kai Ma
- Department of General Surgery, Shandong Qianfoshan Hospital, Cheeloo College of MedicineShandong UniversityJinanShandong ProvinceP.R. China
| | - Zhaowei Sun
- Department of Hepatopancreatobiliary SurgeryThe Affiliated Hospital of Qingdao UniversityQingdaoShandong ProvinceP.R. China
| | - Xueliang Li
- Department of Hepatopancreatobiliary SurgeryThe Affiliated Hospital of Qingdao UniversityQingdaoShandong ProvinceP.R. China
| | - Jingyun Guo
- Department of Hepatopancreatobiliary SurgeryThe Affiliated Hospital of Qingdao UniversityQingdaoShandong ProvinceP.R. China
| | - Qinlei Wang
- Department of Hepatopancreatobiliary SurgeryThe Affiliated Hospital of Qingdao UniversityQingdaoShandong ProvinceP.R. China
| | - Mujian Teng
- Department of General Surgery, Shandong Qianfoshan Hospital, Cheeloo College of MedicineShandong UniversityJinanShandong ProvinceP.R. China
| |
Collapse
|
|
32
|
Metabolic guidance and stress in tumors modulate antigen-presenting cells. Oncogenesis 2022; 11:62. [PMID: 36244976 PMCID: PMC9573874 DOI: 10.1038/s41389-022-00438-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 09/02/2022] [Accepted: 09/30/2022] [Indexed: 11/08/2022] Open
Abstract
Successful antitumor immunity largely relies on efficient T cell priming by antigen-presenting cells (APCs); however, the capacity of APCs is found to be defective in many cancers. Metabolically reprogrammed cancer cells support the energetic and biosynthetic demands of their high proliferation rates by exploiting nutrients available in the tumor microenvironment (TME), which in turn limits proper metabolic reprogramming of APCs during recruitment, differentiation, activation and antigen presentation. Furthermore, some metabolites generated by the TME are unfavorable to antitumor immunity. This review summarizes recent studies on the metabolic features of APCs and their functionality in the TME. Particularly, we will describe how APCs respond to altered TME and how metabolic byproducts from cancer and immunomodulatory cells affect APCs. Finally, we introduce the current status of APC-oriented research and clinical trials targeting metabolic features to boost efficient immunotherapy.
Collapse
|
|
33
|
Tabowei G, Gaddipati GN, Mukhtar M, Alzubaidee MJ, Dwarampudi RS, Mathew S, Bichenapally S, Khachatryan V, Muazzam A, Hamal C, Velugoti LSDR, Mohammed L. Microbiota Dysbiosis a Cause of Colorectal Cancer or Not? A Systematic Review. Cureus 2022; 14:e30893. [PMID: 36465770 PMCID: PMC9711892 DOI: 10.7759/cureus.30893] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 10/30/2022] [Indexed: 11/07/2022] Open
Abstract
Deaths from colorectal cancer (CRC) are still rising, and various links to etiology have been proposed. However, a direct link between microbial dysbiosis and colorectal cancer has not been postulated. This study aimed to identify the role of microbes in the pathogenesis of colorectal cancer. This systematic review was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search was done considering papers published over the past 12 years, using PubMed, PubMed Central, Cochrane, Google Scholar, and ScienceDirect databases. Studies were selected based on the following predefined eligibility criteria: English-language systematic reviews, meta-analysis, randomized controlled trials (RCTs), and clinical trials, which included papers on microbes playing roles in colorectal cancer with the derived data transferred to a template. Following this, quality assessment was done using each study's relevant assessment tool. The initial search generated 128 studies. From the study, we found the ratio of Fusobacterium, when compared between healthy and colorectal cancer patients' guts, was the highest, although it was not the most predominant gut organism. Enterotoxigenic Bacteroides fragilis (ETBF), Clostridium and Salmonella, and Peptostreptococcus showed links with colorectal cancer and described pathways that could explain its implication in colorectal cancer. However, overt conclusions cannot be drawn because further research needs to be conducted.
Collapse
Affiliation(s)
- Godfrey Tabowei
- Department of Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Greeshma N Gaddipati
- Department of Research, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Maria Mukhtar
- Department of Research, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Mohammed J Alzubaidee
- Department of Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Raga Sruthi Dwarampudi
- Department of Research, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Sheena Mathew
- Department of Research, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Sumahitha Bichenapally
- Department of Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Vahe Khachatryan
- Department of Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Asmaa Muazzam
- Department of Pathology Research, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Chandani Hamal
- Department of Internal Medicine/Department of Family Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | | | - Lubna Mohammed
- Department of Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| |
Collapse
|
|
34
|
Wei C, Ma Y, Wang F, Liao Y, Chen Y, Zhao B, Zhao Q, Wang D, Tang D. Igniting Hope for Tumor Immunotherapy: Promoting the "Hot and Cold" Tumor Transition. Clin Med Insights Oncol 2022; 16:11795549221120708. [PMID: 36147198 PMCID: PMC9486259 DOI: 10.1177/11795549221120708] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 08/05/2022] [Indexed: 12/02/2022] Open
Abstract
The discovery of immune checkpoint inhibitors (ICIs) has ushered a new era for immunotherapy against malignant tumors through the killing effects of cytotoxic T lymphocytes in the tumor microenvironment (TME), resulting in long-lasting tumor suppression and regression. Nevertheless, given that ICIs are highly dependent on T cells in the TME and that most tumors lack T-cell infiltration, promoting the conversion of such immunosuppressive "cold" tumors to "hot" tumors is currently a key challenge in tumor immunotherapy. Herein, we systematically outlined the mechanisms underlying the formation of the immunosuppressive TME in cold tumors, including the role of immunosuppressive cells, impaired antigen presentation, transforming growth factor-β, STAT3 signaling, adenosine, and interferon-γ signaling. Moreover, therapeutic strategies for promoting cold tumors to hot tumors with adequate T-cell infiltration were also discussed. Finally, the prospects of therapeutic tools such as oncolytic viruses, nanoparticles, and photothermal therapy in restoring immune activity in cold tumors were thoroughly reviewed.
Collapse
Affiliation(s)
- Chen Wei
- Clinical Medical College, Yangzhou
University, Yangzhou, China
| | - Yichao Ma
- Clinical Medical College, Yangzhou
University, Yangzhou, China
| | - Fei Wang
- Clinical Medical College, Dalian
Medical University, Dalian, China
| | - Yiqun Liao
- Clinical Medical College, Dalian
Medical University, Dalian, China
| | - Yuji Chen
- Clinical Medical College, Yangzhou
University, Yangzhou, China
| | - Bin Zhao
- Clinical Medical College, Dalian
Medical University, Dalian, China
| | - Qi Zhao
- Clinical Medical College, Yangzhou
University, Yangzhou, China
| | - Daorong Wang
- Department of General Surgery,
Institute of General Surgery, Clinical Medical College, Northern Jiangsu People’s
Hospital, Yangzhou University, Yangzhou, China
| | - Dong Tang
- Department of General Surgery,
Institute of General Surgery, Clinical Medical College, Northern Jiangsu People’s
Hospital, Yangzhou University, Yangzhou, China
| |
Collapse
|
|
35
|
Bhat AA, Nisar S, Singh M, Ashraf B, Masoodi T, Prasad CP, Sharma A, Maacha S, Karedath T, Hashem S, Yasin SB, Bagga P, Reddy R, Frennaux MP, Uddin S, Dhawan P, Haris M, Macha MA. Cytokine- and chemokine-induced inflammatory colorectal tumor microenvironment: Emerging avenue for targeted therapy. Cancer Commun (Lond) 2022; 42:689-715. [PMID: 35791509 PMCID: PMC9395317 DOI: 10.1002/cac2.12295] [Citation(s) in RCA: 100] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/28/2022] [Accepted: 04/24/2022] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is a predominant life-threatening cancer, with liver and peritoneal metastases as the primary causes of death. Intestinal inflammation, a known CRC risk factor, nurtures a local inflammatory environment enriched with tumor cells, endothelial cells, immune cells, cancer-associated fibroblasts, immunosuppressive cells, and secretory growth factors. The complex interactions of aberrantly expressed cytokines, chemokines, growth factors, and matrix-remodeling enzymes promote CRC pathogenesis and evoke systemic responses that affect disease outcomes. Mounting evidence suggests that these cytokines and chemokines play a role in the progression of CRC through immunosuppression and modulation of the tumor microenvironment, which is partly achieved by the recruitment of immunosuppressive cells. These cells impart features such as cancer stem cell-like properties, drug resistance, invasion, and formation of the premetastatic niche in distant organs, promoting metastasis and aggressive CRC growth. A deeper understanding of the cytokine- and chemokine-mediated signaling networks that link tumor progression and metastasis will provide insights into the mechanistic details of disease aggressiveness and facilitate the development of novel therapeutics for CRC. Here, we summarized the current knowledge of cytokine- and chemokine-mediated crosstalk in the inflammatory tumor microenvironment, which drives immunosuppression, resistance to therapeutics, and metastasis during CRC progression. We also outlined the potential of this crosstalk as a novel therapeutic target for CRC. The major cytokine/chemokine pathways involved in cancer immunotherapy are also discussed in this review.
Collapse
Affiliation(s)
- Ajaz A. Bhat
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Sabah Nisar
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Mayank Singh
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Bazella Ashraf
- Department of BiotechnologySchool of Life SciencesCentral University of KashmirGanderbalJammu & Kashmir191201India
| | - Tariq Masoodi
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Chandra P. Prasad
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Atul Sharma
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Selma Maacha
- Division of Translational MedicineResearch BranchSidra MedicineDoha26999Qatar
| | | | - Sheema Hashem
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Syed Besina Yasin
- Department of PathologySher‐I‐Kashmir Institute of Medical SciencesSrinagarJammu & Kashmir190011India
| | - Puneet Bagga
- Department of Diagnostic ImagingSt. Jude Children's Research HospitalMemphisTN38105USA
| | - Ravinder Reddy
- Center for Advanced Metabolic Imaging in Precision MedicineDepartment of RadiologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPA19104USA
| | | | - Shahab Uddin
- Translational Research InstituteHamad Medical CorporationDoha3050Qatar
| | - Punita Dhawan
- Department of Biochemistry and Molecular BiologyUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Mohammad Haris
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
- Laboratory Animal Research CenterQatar UniversityDoha2713Qatar
| | - Muzafar A. Macha
- Watson‐Crick Centre for Molecular MedicineIslamic University of Science and TechnologyAwantiporaJammu & Kashmir192122India
| |
Collapse
|
|
36
|
Aristin Revilla S, Kranenburg O, Coffer PJ. Colorectal Cancer-Infiltrating Regulatory T Cells: Functional Heterogeneity, Metabolic Adaptation, and Therapeutic Targeting. Front Immunol 2022; 13:903564. [PMID: 35874729 PMCID: PMC9304750 DOI: 10.3389/fimmu.2022.903564] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 06/06/2022] [Indexed: 11/18/2022] Open
Abstract
Colorectal cancer (CRC) is a heterogeneous disease with one of the highest rates of incidence and mortality among cancers worldwide. Understanding the CRC tumor microenvironment (TME) is essential to improve diagnosis and treatment. Within the CRC TME, tumor-infiltrating lymphocytes (TILs) consist of a heterogeneous mixture of adaptive immune cells composed of mainly anti-tumor effector T cells (CD4+ and CD8+ subpopulations), and suppressive regulatory CD4+ T (Treg) cells. The balance between these two populations is critical in anti-tumor immunity. In general, while tumor antigen-specific T cell responses are observed, tumor clearance frequently does not occur. Treg cells are considered to play an important role in tumor immune escape by hampering effective anti-tumor immune responses. Therefore, CRC-tumors with increased numbers of Treg cells have been associated with promoting tumor development, immunotherapy failure, and a poorer prognosis. Enrichment of Treg cells in CRC can have multiple causes including their differentiation, recruitment, and preferential transcriptional and metabolic adaptation to the TME. Targeting tumor-associated Treg cell may be an effective addition to current immunotherapy approaches. Strategies for depleting Treg cells, such as low-dose cyclophosphamide treatment, or targeting one or more checkpoint receptors such as CTLA-4 with PD-1 with monoclonal antibodies, have been explored. These have resulted in activation of anti-tumor immune responses in CRC-patients. Overall, it seems likely that CRC-associated Treg cells play an important role in determining the success of such therapeutic approaches. Here, we review our understanding of the role of Treg cells in CRC, the possible mechanisms that support their homeostasis in the tumor microenvironment, and current approaches for manipulating Treg cells function in cancer.
Collapse
Affiliation(s)
- Sonia Aristin Revilla
- Center Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
- Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, Netherlands
- Laboratory Translational Oncology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Onno Kranenburg
- Laboratory Translational Oncology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Paul J. Coffer
- Center Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
- Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, Netherlands
- *Correspondence: Paul J. Coffer,
| |
Collapse
|
|
37
|
Austermann J, Roth J, Barczyk-Kahlert K. The Good and the Bad: Monocytes' and Macrophages' Diverse Functions in Inflammation. Cells 2022; 11:cells11121979. [PMID: 35741108 PMCID: PMC9222172 DOI: 10.3390/cells11121979] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/08/2022] [Accepted: 06/16/2022] [Indexed: 02/06/2023] Open
Abstract
Monocytes and macrophages are central players of the innate immune response and play a pivotal role in the regulation of inflammation. Thereby, they actively participate in all phases of the immune response, from initiating inflammation and triggering the adaptive immune response, through to the clearance of cell debris and resolution of inflammation. In this review, we described the mechanisms of monocyte and macrophage adaptation to rapidly changing microenvironmental conditions and discussed different forms of macrophage polarization depending on the environmental cues or pathophysiological condition. Therefore, special focus was placed on the tight regulation of the pro- and anti-inflammatory immune response, and the diverse functions of S100A8/S100A9 proteins and the scavenger receptor CD163 were highlighted, respectively. We paid special attention to the function of pro- and anti-inflammatory macrophages under pathological conditions.
Collapse
|
|
38
|
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
|
|
39
|
Su S, Lei A, Wang X, Lu H, Wang S, Yang Y, Li N, Zhang Y, Zhang J. Induced CAR-Macrophages as a Novel Therapeutic Cell Type for Cancer Immune Cell Therapies. Cells 2022; 11:1652. [PMID: 35626689 PMCID: PMC9139529 DOI: 10.3390/cells11101652] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 04/09/2022] [Accepted: 04/22/2022] [Indexed: 01/27/2023] Open
Abstract
The Chimeric antigen receptor (CAR)-T cell therapy has made inroads in treating hematological malignancies. Nonetheless, there are still multiple hurdles in CAR-T cell therapy for solid tumors. Primary CAR-expressing macrophage cells (CAR-Ms) and induced pluripotent stem cells (iPSCs)-derived CAR-expressing macrophage cells (CAR-iMacs) have emerged as attractive alternatives in our quest for an efficient and inexpensive approach for tumor immune cell therapy. In this review, we list the current state of development of human CAR-macrophages and provide an overview of the crucial functions of human CAR-macrophages in the field of tumor immune cell therapy.
Collapse
Affiliation(s)
- Siyu Su
- Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou 362000, China;
- Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou 311121, China; (A.L.); (X.W.); (H.L.)
| | - Anhua Lei
- Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou 311121, China; (A.L.); (X.W.); (H.L.)
- Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
- Institute of Hematology, Zhejiang University, Hangzhou 310058, China
| | - Xudong Wang
- Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou 311121, China; (A.L.); (X.W.); (H.L.)
- Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
- Institute of Hematology, Zhejiang University, Hangzhou 310058, China
| | - Hengxing Lu
- Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou 311121, China; (A.L.); (X.W.); (H.L.)
| | - Shuhang Wang
- National Cancer Center/National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan, Beijing 100021, China; (S.W.); (N.L.)
| | - Yuqi Yang
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People’s Hospital, No. 83 Zhongshan Road, Guiyang 550000, China;
| | - Ning Li
- National Cancer Center/National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan, Beijing 100021, China; (S.W.); (N.L.)
| | - Yi Zhang
- Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou 362000, China;
| | - Jin Zhang
- Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou 311121, China; (A.L.); (X.W.); (H.L.)
- Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
- Institute of Hematology, Zhejiang University, Hangzhou 310058, China
| |
Collapse
|
|
40
|
Wong NKY, Dong X, Lin YY, Xue H, Wu R, Lin D, Collins C, Wang Y. Framework of Intrinsic Immune Landscape of Dormant Prostate Cancer. Cells 2022; 11:cells11091550. [PMID: 35563856 PMCID: PMC9105276 DOI: 10.3390/cells11091550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/30/2022] [Accepted: 05/03/2022] [Indexed: 02/01/2023] Open
Abstract
Androgen deprivation therapy (ADT) is the standard therapy for men with advanced prostate cancer (PCa). PCa often responds to ADT and enters a dormancy period, which can be recognized clinically as a minimal residual disease. However, the majority of these patients will eventually experience a relapse in the form of castration-resistant PCa with poor survival. Therefore, ADT-induced dormancy is a unique time window for treatment that can provide a cure. The study of this well-recognized phase of prostate cancer progression is largely hindered by the scarcity of appropriate clinical tissue and clinically relevant preclinical models. Here, we report the utility of unique and clinically relevant patient-derived xenograft models in the study of the intrinsic immune landscape of dormant PCa. Using data from RNA sequencing, we have reconstructed the immune evasion mechanisms that can be utilized by dormant PCa cells. Since dormant PCa cells need to evade the host immune surveillance for survival, our results provide a framework for further study and for devising immunomodulatory mechanisms that can eliminate dormant PCa cells.
Collapse
Affiliation(s)
- Nelson K. Y. Wong
- Department of Experimental Therapeutics, BC Cancer, 675 W 10th Ave, Vancouver, BC V5Z 1L3 Canada; (N.K.Y.W.); (X.D.); (H.X.); (R.W.); (D.L.)
| | - Xin Dong
- Department of Experimental Therapeutics, BC Cancer, 675 W 10th Ave, Vancouver, BC V5Z 1L3 Canada; (N.K.Y.W.); (X.D.); (H.X.); (R.W.); (D.L.)
| | - Yen-Yi Lin
- Vancouver Prostate Centre, Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; (Y.-Y.L.); (C.C.)
| | - Hui Xue
- Department of Experimental Therapeutics, BC Cancer, 675 W 10th Ave, Vancouver, BC V5Z 1L3 Canada; (N.K.Y.W.); (X.D.); (H.X.); (R.W.); (D.L.)
| | - Rebecca Wu
- Department of Experimental Therapeutics, BC Cancer, 675 W 10th Ave, Vancouver, BC V5Z 1L3 Canada; (N.K.Y.W.); (X.D.); (H.X.); (R.W.); (D.L.)
| | - Dong Lin
- Department of Experimental Therapeutics, BC Cancer, 675 W 10th Ave, Vancouver, BC V5Z 1L3 Canada; (N.K.Y.W.); (X.D.); (H.X.); (R.W.); (D.L.)
| | - Colin Collins
- Vancouver Prostate Centre, Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; (Y.-Y.L.); (C.C.)
| | - Yuzhuo Wang
- Department of Experimental Therapeutics, BC Cancer, 675 W 10th Ave, Vancouver, BC V5Z 1L3 Canada; (N.K.Y.W.); (X.D.); (H.X.); (R.W.); (D.L.)
- Vancouver Prostate Centre, Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; (Y.-Y.L.); (C.C.)
- Correspondence: ; Tel.: +1-604-675-8013
| |
Collapse
|
|
41
|
Pernot S, Evrard S, Khatib AM. The Give-and-Take Interaction Between the Tumor Microenvironment and Immune Cells Regulating Tumor Progression and Repression. Front Immunol 2022; 13:850856. [PMID: 35493456 PMCID: PMC9043524 DOI: 10.3389/fimmu.2022.850856] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 03/28/2022] [Indexed: 11/29/2022] Open
Abstract
A fundamental concern of the majority of cancer scientists is related to the identification of mechanisms involved in the evolution of neoplastic cells at the cellular and molecular level and how these processes are able to control cancer cells appearance and death. In addition to the genome contribution, such mechanisms involve reciprocal interactions between tumor cells and stromal cells within the tumor microenvironment (TME). Indeed, tumor cells survival and growth rely on dynamic properties controlling pro and anti-tumorigenic processes. The anti-tumorigenic function of the TME is mainly regulated by immune cells such as dendritic cells, natural killer cells, cytotoxic T cells and macrophages and normal fibroblasts. The pro-tumorigenic function is also mediated by other immune cells such as myeloid-derived suppressor cells, M2-tumor-associated macrophages (TAMs) and regulatory T (Treg) cells, as well as carcinoma-associated fibroblasts (CAFs), adipocytes (CAA) and endothelial cells. Several of these cells can show both, pro- and antitumorigenic activity. Here we highlight the importance of the reciprocal interactions between tumor cells and stromal cells in the self-centered behavior of cancer cells and how these complex cellular interactions control tumor progression and repression.
Collapse
Affiliation(s)
- Simon Pernot
- Reprograming Tumor Activity and Associated Microenvironment (RYTME), Bordeaux Institute of Oncology (BRIC)-Unité Mixte de Recherche (UMR) 1312 Inserm, Pessac, France
| | | | - Abdel-Majid Khatib
- Reprograming Tumor Activity and Associated Microenvironment (RYTME), Bordeaux Institute of Oncology (BRIC)-Unité Mixte de Recherche (UMR) 1312 Inserm, Pessac, France.,Institut Bergonié, Bordeaux, France
| |
Collapse
|
|
42
|
Dobroch J, Bojczuk K, Kołakowski A, Baczewska M, Knapp P. The Exploration of Chemokines Importance in the Pathogenesis and Development of Endometrial Cancer. Molecules 2022; 27:2041. [PMID: 35408440 PMCID: PMC9000631 DOI: 10.3390/molecules27072041] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/13/2022] [Accepted: 03/18/2022] [Indexed: 01/10/2023] Open
Abstract
Endometrial cancer (EC) is one of the most frequent female malignancies. Because of a characteristic symptom, vaginal bleeding, EC is often diagnosed in an early stage. Despite that, some EC cases present an atypical course with rapid progression and poor prognosis. There have been multiple studies conducted on molecular profiling of EC in order to improve diagnostics and introduce personalized treatment. Chemokines-a protein family that contributes to inflammatory processes that may promote carcinogenesis-constitute an area of interest. Some chemokines and their receptors present alterations in expression in tumor microenvironment. CXCL12, which binds the receptors CXCR4 and CXCR7, is known for its impact on neoplastic cell proliferation, neovascularization and promotion of epidermal-mesenchymal transition. The CCL2-CCR2 axis additionally plays a pivotal role in EC with mutations in the LKB1 gene and activates tumor-associated macrophages. CCL20 and CCR6 are influenced by the RANK/RANKL pathway and alter the function of lymphocytes and dendritic cells. Another axis, CXCL10-CXCR3, affects the function of NK-cells and, interestingly, presents different roles in various types of tumors. This review article consists of analysis of studies that included the roles of the aforementioned chemokines in EC pathogenesis. Alterations in chemokine expression are described, and possible applications of drugs targeting chemokines are reviewed.
Collapse
Affiliation(s)
- Jakub Dobroch
- Department of Gynecology and Gynecologic Oncology, Medical University of Bialystok, 15-089 Bialystok, Poland; (K.B.); (A.K.); (M.B.); (P.K.)
- University Oncology Center, University Clinical Hospital in Bialystok, 15-276 Bialystok, Poland
| | - Klaudia Bojczuk
- Department of Gynecology and Gynecologic Oncology, Medical University of Bialystok, 15-089 Bialystok, Poland; (K.B.); (A.K.); (M.B.); (P.K.)
| | - Adrian Kołakowski
- Department of Gynecology and Gynecologic Oncology, Medical University of Bialystok, 15-089 Bialystok, Poland; (K.B.); (A.K.); (M.B.); (P.K.)
| | - Marta Baczewska
- Department of Gynecology and Gynecologic Oncology, Medical University of Bialystok, 15-089 Bialystok, Poland; (K.B.); (A.K.); (M.B.); (P.K.)
- University Oncology Center, University Clinical Hospital in Bialystok, 15-276 Bialystok, Poland
| | - Paweł Knapp
- Department of Gynecology and Gynecologic Oncology, Medical University of Bialystok, 15-089 Bialystok, Poland; (K.B.); (A.K.); (M.B.); (P.K.)
- University Oncology Center, University Clinical Hospital in Bialystok, 15-276 Bialystok, Poland
| |
Collapse
|
|
43
|
Wu D, Liu X, Mu J, Yang J, Wu F, Zhou H. Therapeutic Approaches Targeting Proteins in Tumor-Associated Macrophages and Their Applications in Cancers. Biomolecules 2022; 12:biom12030392. [PMID: 35327584 PMCID: PMC8945446 DOI: 10.3390/biom12030392] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 02/11/2022] [Accepted: 02/28/2022] [Indexed: 02/07/2023] Open
Abstract
Tumor-associated macrophages (TAMs) promote tumor proliferation, invasion, angiogenesis, stemness, therapeutic resistance, and immune tolerance in a protein-dependent manner. Therefore, the traditional target paradigms are often insufficient to exterminate tumor cells. These pro-tumoral functions are mediated by the subsets of macrophages that exhibit canonical protein markers, while simultaneously having unique transcriptional features, which makes the proteins expressed on TAMs promising targets during anti-tumor therapy. Herein, TAM-associated protein-dependent target strategies were developed with the aim of either reducing the numbers of TAMs or inhibiting the pro-tumoral functions of TAMs. Furthermore, the recent advances in TAMs associated with tumor metabolism and immunity were extensively exploited to repolarize these TAMs to become anti-tumor elements and reverse the immunosuppressive tumor microenvironment. In this review, we systematically summarize these current studies to fully illustrate the TAM-associated protein targets and their inhibitors, and we highlight the potential clinical applications of targeting the crosstalk among TAMs, tumor cells, and immune cells in anti-tumor therapy.
Collapse
Affiliation(s)
- Deyang Wu
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, Frontier Innovation Center for Dental Medicine Plus, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; (D.W.); (J.M.); (J.Y.)
| | - Xiaowei Liu
- State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu 610041, China;
| | - Jingtian Mu
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, Frontier Innovation Center for Dental Medicine Plus, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; (D.W.); (J.M.); (J.Y.)
| | - Jin Yang
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, Frontier Innovation Center for Dental Medicine Plus, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; (D.W.); (J.M.); (J.Y.)
| | - Fanglong Wu
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, Frontier Innovation Center for Dental Medicine Plus, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; (D.W.); (J.M.); (J.Y.)
- Correspondence: (F.W.); (H.Z.)
| | - Hongmei Zhou
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, Frontier Innovation Center for Dental Medicine Plus, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; (D.W.); (J.M.); (J.Y.)
- Correspondence: (F.W.); (H.Z.)
| |
Collapse
|
|
44
|
Haegebaert RM, Kempers M, Ceelen W, Lentacker I, Remaut K. Nanoparticle mediated targeting of toll-like receptors to treat colorectal cancer. Eur J Pharm Biopharm 2022; 172:16-30. [PMID: 35074555 DOI: 10.1016/j.ejpb.2022.01.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 12/16/2021] [Accepted: 01/17/2022] [Indexed: 02/07/2023]
|
|
45
|
Jung M, Kang M, Kim BS, Hong J, Kim C, Koh CH, Choi G, Chung Y, Kim BS. Nanovesicle-Mediated Targeted Delivery of Immune Checkpoint Blockades to Potentiate Therapeutic Efficacy and Prevent Side Effects. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2106516. [PMID: 34962660 DOI: 10.1002/adma.202106516] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 12/22/2021] [Indexed: 06/14/2023]
Abstract
Despite the clinically proven efficacies of immune checkpoint blockades, including anti-cytotoxic T lymphocyte-associated protein 4 antibody (αCTLA-4), the low response rate and immune-related adverse events (irAEs) in cancer patients represent major drawbacks of the therapy. These drawbacks of αCTLA-4 therapy are mainly due to the suboptimal activation of tumor-specific cytotoxic T lymphocytes (CTLs) and the systemic nonspecific activation of T cells. To overcome such drawbacks, αCTLA-4 is delivered by dendritic cell-derived nanovesicles presenting tumor antigens (DCNV-TAs) that exclusively interact with tumor-specific T cells, leading to selective activation of tumor-specific CTLs. Compared to conventional αCTLA-4 therapy, treatment with αCTLA-4-conjugated DCNV-TAs significantly inhibits tumor growth and reduces irAEs in syngeneic tumor-bearing mice. This study demonstrates that the spatiotemporal presentation of both αCTLA-4 and tumor antigens enables selective activation of tumor-specific T cells and potentiates the antitumor efficacy of αCTLA-4 without inducing systemic irAEs.
Collapse
Affiliation(s)
- Mungyo Jung
- School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Mikyung Kang
- Interdisciplinary Program for Bioengineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Byung-Seok Kim
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
- Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon, 22012, Republic of Korea
| | - Jihye Hong
- Interdisciplinary Program for Bioengineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Cheesue Kim
- School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Choong-Hyun Koh
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Garam Choi
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Yeonseok Chung
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Byung-Soo Kim
- School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea
- Interdisciplinary Program for Bioengineering, Seoul National University, Seoul, 08826, Republic of Korea
- Institute of Chemical Processes, Institute of Engineering Research, and BioMAX, Seoul National University, Seoul, 08826, Republic of Korea
| |
Collapse
|
|
46
|
Kwantwi LB, Wang S, Sheng Y, Wu Q. Multifaceted roles of CCL20 (C-C motif chemokine ligand 20): mechanisms and communication networks in breast cancer progression. Bioengineered 2021; 12:6923-6934. [PMID: 34569432 PMCID: PMC8806797 DOI: 10.1080/21655979.2021.1974765] [Citation(s) in RCA: 29] [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: 07/15/2021] [Accepted: 08/20/2021] [Indexed: 12/12/2022] Open
Abstract
Emerging studies have demonstrated notable roles of CCL20 in breast cancer progression. Based on these findings, CCL20 has become a potential therapeutic target for cancer immunotherapy. Accordingly, studies utilizing monoclonal antibodies to target CCL20 are currently being experimented. However, the existence of cytokine network in the tumor microenvironment collectively regulates tumor progression. Hence, a deeper understanding of the role of CCL20 and the underlying signaling pathways regulating the functions of CCL20 may provide a novel strategy for therapeutic interventions. This review provides the current knowledge on how CCL20 interacts with breast cancer cells to influence tumor progression via immunosuppression, angiogenesis, epithelial to mesenchymal transition, migration/invasion and chemoresistance. As a possible candidate biomarker, we also reviewed signal pathways and other factors in the tumor microenvironment regulating the tumor-promoting functions of CCL20.These new insights may be useful to design new potent and selective CCL20 inhibitors against breast cancer in the future.
Collapse
Affiliation(s)
- Louis Boafo Kwantwi
- Department of Pathology, School of Basic Medical Science, Anhui Medical University, Hefei, PR China
| | - Shujing Wang
- Department of Pathology, School of Basic Medical Science, Anhui Medical University, Hefei, PR China
- Department of Immunology, School of Basic Medical Science, Anhui Medical University, Hefei, PR China
| | - Youjing Sheng
- Department of Pathology, School of Basic Medical Science, Anhui Medical University, Hefei, PR China
| | - Qiang Wu
- Department of Pathology, School of Basic Medical Science, Anhui Medical University, Hefei, PR China
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, PR China
| |
Collapse
|
|
47
|
CCL20 induces colorectal cancer neoplastic epithelial cell proliferation, migration, and further CCL20 production through autocrine HGF-c-Met and MSP-MSPR signaling pathways. Oncotarget 2021; 12:2323-2337. [PMID: 34853656 PMCID: PMC8629403 DOI: 10.18632/oncotarget.28131] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 09/28/2021] [Indexed: 12/16/2022] Open
Abstract
CCL20-CCR6 interactions promote colorectal cancer through direct effects on neoplastic epithelial cells and through modulating the tumor microenvironment. The mechanism of these effects on neoplastic epithelial cells is poorly understood. This study demonstrates that CCL20 induces secretion of hepatocyte growth factor (HGF) and phosphorylation of HGF’s cognate receptor c-Met in HT29 and HCT116 colorectal cancer cell lines both in concentration- and time-dependent manners. Similar to CCL20, HGF induces migration, autofeedback CCL20 secretion, and ERK1/2 phosphorylation in the colon cancer cells. CCL20-dependent ERK1/2 phosphorylation is blocked by HGF inhibition, and CCL20-dependent migration and CCL20 secretion are blocked by inhibition of HGF or ERK. Interestingly, unlike CCL20, HGF does not induce proliferation of colon cancer cells, and CCL20-dependent cell proliferation is not blocked by direct HGF inhibition. CCL20-dependent proliferation, however, is blocked by the multi-tyrosine kinase inhibitor crizotinib. Exploring this effect, it was found that CCL20 also induces production of MSP and phosphorylation of MSP’s receptor MSPR by the colorectal cancer cells. CCL20-dependent cell proliferation is inhibited by directly blocking MSP-MSPR interactions. Thus, CCL20-mediated migration and CCL20 secretion are regulated through a pathway involving HGF, c-Met, and ERK, while CCL20-mediated proliferation is instead regulated through MSP and its receptor MSPR.
Collapse
|
|
48
|
Datsi A, Sorg RV. Dendritic Cell Vaccination of Glioblastoma: Road to Success or Dead End. Front Immunol 2021; 12:770390. [PMID: 34795675 PMCID: PMC8592940 DOI: 10.3389/fimmu.2021.770390] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 10/11/2021] [Indexed: 12/11/2022] Open
Abstract
Glioblastomas (GBM) are the most frequent and aggressive malignant primary brain tumor and remains a therapeutic challenge: even after multimodal therapy, median survival of patients is only 15 months. Dendritic cell vaccination (DCV) is an active immunotherapy that aims at inducing an antitumoral immune response. Numerous DCV trials have been performed, vaccinating hundreds of GBM patients and confirming feasibility and safety. Many of these studies reported induction of an antitumoral immune response and indicated improved survival after DCV. However, two controlled randomized trials failed to detect a survival benefit. This raises the question of whether the promising concept of DCV may not hold true or whether we are not yet realizing the full potential of this therapeutic approach. Here, we discuss the results of recent vaccination trials, relevant parameters of the vaccines themselves and of their application, and possible synergies between DCV and other therapeutic approaches targeting the immunosuppressive microenvironment of GBM.
Collapse
Affiliation(s)
- Angeliki Datsi
- Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine University Hospital, Medical Faculty, Düsseldorf, Germany
| | - Rüdiger V Sorg
- Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine University Hospital, Medical Faculty, Düsseldorf, Germany
| |
Collapse
|
|
49
|
Marques HS, de Brito BB, da Silva FAF, Santos MLC, de Souza JCB, Correia TML, Lopes LW, Neres NSDM, Dórea RSDM, Dantas ACS, Morbeck LLB, Lima IS, de Almeida AA, Dias MRDJ, de Melo FF. Relationship between Th17 immune response and cancer. World J Clin Oncol 2021; 12:845-867. [PMID: 34733609 PMCID: PMC8546660 DOI: 10.5306/wjco.v12.i10.845] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 07/21/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
Cancer is the second leading cause of death worldwide and epidemiological projections predict growing cancer mortality rates in the next decades. Cancer has a close relationship with the immune system and, although Th17 cells are known to play roles in the immune response against microorganisms and in autoimmunity, studies have emphasized their roles in cancer pathogenesis. The Th17 immune response profile is involved in several types of cancer including urogenital, respiratory, gastrointestinal, and skin cancers. This type of immune response exerts pro and antitumor functions through several mechanisms, depending on the context of each tumor, including the protumor angiogenesis and exhaustion of T cells and the antitumor recruitment of T cells and neutrophils to the tumor microenvironment. Among other factors, the paradoxical behavior of Th17 cells in this setting has been attributed to its plasticity potential, which makes possible their conversion into other types of T cells such as Th17/Treg and Th17/Th1 cells. Interleukin (IL)-17 stands out among Th17-related cytokines since it modulates pathways and interacts with other cell profiles in the tumor microenvironment, which allow Th17 cells to prevail in tumors. Moreover, the IL-17 is able to mediate pro and antitumor processes that influence the development and progression of various cancers, being associated with variable clinical outcomes. The understanding of the relationship between the Th17 immune response and cancer as well as the singularities of carcinogenic processes in each type of tumor is crucial for the identification of new therapeutic targets.
Collapse
Affiliation(s)
- Hanna Santos Marques
- Campus Vitória da Conquista, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista 45083-900, Bahia, Brazil
| | - Breno Bittencourt de Brito
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Maria Luísa Cordeiro Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Júlio César Braga de Souza
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Thiago Macêdo Lopes Correia
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Luana Weber Lopes
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Nayara Silva de Macêdo Neres
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Anna Carolina Saúde Dantas
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Lorena Lôbo Brito Morbeck
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Iasmin Souza Lima
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Amanda Alves de Almeida
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Maiara Raulina de Jesus Dias
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| |
Collapse
|
|
50
|
Abstract
Tumor-associated macrophages (TAMs) represent the most abundant leukocyte population in most solid tumors and are greatly influenced by the tumor microenvironment. More importantly, these macrophages can promote tumor growth and metastasis through interactions with other cell populations within the tumor milieu and have been associated with poor outcomes in multiple tumors. In this review, we examine how the tumor microenvironment facilitates the polarization of TAMs. Additionally, we evaluate the mechanisms by which TAMs promote tumor angiogenesis, induce tumor invasion and metastasis, enhance chemotherapeutic resistance, and foster immune evasion. Lastly, we focus on therapeutic strategies that target TAMs in the treatments of cancer, including reducing monocyte recruitment, depleting or reprogramming TAMs, and targeting inhibitory molecules to increase TAM-mediated phagocytosis.
Collapse
Affiliation(s)
- Amy J Petty
- Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
| | - Dwight H Owen
- Division of Medical Oncology, Department of Internal Medicine, College of Medicine and OSU Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Yiping Yang
- Division of Hematology, Department of Internal Medicine, College of Medicine and OSU Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Xiaopei Huang
- Division of Hematology, Department of Internal Medicine, College of Medicine and OSU Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| |
Collapse
|