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Chi J, Gao Q, Liu D. Tissue-Resident Macrophages in Cancer: Friend or Foe? Cancer Med 2024; 13:e70387. [PMID: 39494816 PMCID: PMC11533131 DOI: 10.1002/cam4.70387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 10/15/2024] [Accepted: 10/20/2024] [Indexed: 11/05/2024] Open
Abstract
INTRODUCTION Macrophages are essential in maintaining homeostasis, combating infections, and influencing the process of various diseases, including cancer. Macrophages originate from diverse lineages: Notably, tissue-resident macrophages (TRMs) differ from hematopoietic stem cells and circulating monocyte-derived macrophages based on genetics, development, and function. Therefore, understanding the recruited and TRM populations is crucial for investigating disease processes. METHODS By searching literature databses, we summarized recent relevant studies. Research has shown that tumor-associated macrophages (TAMs) of distinct origins accumulate in tumor microenvironment (TME), with TRM-derived TAMs closely resembling gene signatures of normal TRMs. RESULTS Recent studies have revealed that TRMs play a crucial role in cancer progression. However, organ-specific effects complicate TRM investigations. Nonetheless, the precise involvement of TRMs in tumors is unclear. This review explores the multifaceted roles of TRMs in cancer, presenting insights into their origins, proliferation, the latest research methodologies, their impact across various tumor sites, their potential and strategies as therapeutic targets, interactions with other cells within the TME, and the internal heterogeneity of TRMs. CONCLUSIONS We believe that a comprehensive understanding of the multifaceted roles of TRMs will pave the way for targeted TRM therapies in the treatment of cancer.
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Affiliation(s)
- Jianhua Chi
- Department of Obstetrics and GynecologyNational Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and MetastasisTongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Qinglei Gao
- Department of Obstetrics and GynecologyNational Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and MetastasisTongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Dan Liu
- Department of Obstetrics and GynecologyNational Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and MetastasisTongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
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Fan Q, Fu ZW, Xu M, Lv F, Shi JS, Zeng QQ, Xiong DH. Research progress of tumor-associated macrophages in immune checkpoint inhibitor tolerance in colorectal cancer. World J Gastrointest Oncol 2024; 16:4064-4079. [DOI: 10.4251/wjgo.v16.i10.4064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 08/03/2024] [Accepted: 08/16/2024] [Indexed: 09/26/2024] Open
Abstract
The relevant mechanism of tumor-associated macrophages (TAMs) in the treatment of colorectal cancer patients with immune checkpoint inhibitors (ICIs) is discussed, and the application prospects of TAMs in reversing the treatment tolerance of ICIs are discussed to provide a reference for related studies. As a class of drugs widely used in clinical tumor immunotherapy, ICIs can act on regulatory molecules on cells that play an inhibitory role-immune checkpoints-and kill tumors in the form of an immune response by activating a variety of immune cells in the immune system. The sensitivity of patients with different types of colorectal cancer to ICI treatment varies greatly. The phenotype and function of TAMs in the colorectal cancer microenvironment are closely related to the efficacy of ICIs. ICIs can regulate the phenotypic function of TAMs, and TAMs can also affect the tolerance of colorectal cancer to ICI therapy. TAMs play an important role in ICI resistance, and making full use of this target as a therapeutic strategy is expected to improve the immunotherapy efficacy and prognosis of patients with colorectal cancer.
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Affiliation(s)
- Qi Fan
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Zheng-Wei Fu
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Ming Xu
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Feng Lv
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Jia-Song Shi
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Qi-Qi Zeng
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - De-Hai Xiong
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
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Ignacio A, Cipelli M, Takiishi T, Favero Aguiar C, Fernandes Terra F, Ghirotto B, Martins Silva E, Castoldi A, Magalhães YT, Antonio T, Nunes Padovani B, Ioshie Hiyane M, Andrade-Oliveira V, Forti FL, Olsen Saraiva Camara N. Lack of mTORC2 signaling in CD11c+ myeloid cells inhibits their migration and ameliorates experimental colitis. J Leukoc Biol 2024; 116:779-792. [PMID: 38652699 DOI: 10.1093/jleuko/qiae084] [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: 05/24/2023] [Revised: 01/30/2024] [Accepted: 03/05/2024] [Indexed: 04/25/2024] Open
Abstract
The mammalian target of rapamycin (mTOR) pathway plays a key role in determining immune cells function through modulation of their metabolic status. By specific deletion of Rictor in CD11c+ myeloid cells (referred to here as CD11cRicΔ/Δ), we investigated the role of mTOR complex 2 (mTORC2) signaling in dendritic cells (DCs) function in mice. We showed that upon dextran sulfate sodium-induced colitis, the lack of mTORC2 signaling CD11c+ cells diminishes the colitis score and abrogates DC migration to the mesenteric lymph nodes, thereby diminishing the infiltration of T helper 17 cells in the lamina propria and subsequent inflammation. These findings corroborate with the abrogation of cytoskeleton organization and the decreased activation of Rac1 and Cdc42 GTPases observed in CD11c+-mTORC2-deficient cells. Meta-analysis on colonic samples from ulcerative colitis patients revealed increased gene expression of proinflammatory cytokines, which coincided with augmented expression of the mTOR pathway, a positive correlation between the DC marker ITGAX and interleukin-6, the expression of RICTOR, and CDC42. Together, this work proposes that targeting mTORC2 on DCs offers a key to hamper inflammatory responses, and this way, ameliorates the progression and severity of intestinal inflammatory diseases.
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Affiliation(s)
- Aline Ignacio
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Marcella Cipelli
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Tatiane Takiishi
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Cristhiane Favero Aguiar
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Fernanda Fernandes Terra
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Bruno Ghirotto
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Eloisa Martins Silva
- Center for Natural and Human Sciences, Federal University of ABC. Alameda da Universidade (UFABC) 09606045, São Bernardo do Campo, SP, Brazil
| | - Angela Castoldi
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Yuli Thamires Magalhães
- Laboratory of Signaling in Biomolecular Systems, Department of Biochemistry, Institute of Chemistry, University of São Paulo. Av. Prof. Lineu Prestes, 748 05508900, São Paulo, Brazil
| | - Tiago Antonio
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Barbara Nunes Padovani
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Meire Ioshie Hiyane
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Vinicius Andrade-Oliveira
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Fabio Luis Forti
- Laboratory of Signaling in Biomolecular Systems, Department of Biochemistry, Institute of Chemistry, University of São Paulo. Av. Prof. Lineu Prestes, 748 05508900, São Paulo, Brazil
| | - Niels Olsen Saraiva Camara
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
- Laboratory of Renal Physiology, Department of Medicine, Federal University of São Paulo (UNIFESP). Rua Botucatu 740, 04023-062, São Paulo, Brazil
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Zhang Z, Huang H, Peng L, Zhou B, Yang H, Tang Z, Yan W, Chen W, Liu Z, Zheng D, Shen P, Fang W. SIX4 Activation in Inflammatory Response Drives the Transformation of Colorectal Epithelium into Inflammation and Tumor via Feedback-Enhancing Inflammatory Signaling to Induce Tumor Stemness Signaling. Int J Biol Sci 2024; 20:4618-4634. [PMID: 39309424 PMCID: PMC11414381 DOI: 10.7150/ijbs.93411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 07/31/2024] [Indexed: 09/25/2024] Open
Abstract
Some colorectal cancer patients have experienced normal epithelial transformation into inflammatory and tumor states, but the molecular basis still needs to be further determined. The expression levels of SIX4 are gradually increased in dextran sodium sulfate (DSS) and azoxymethane (AOM)/DSS-induced colonic epithelial inflammation and tumors, respectively, in mice. Targeting SIX4 alleviates intestinal inflammation occurrence and reduces adenoma formation in mice. Clinical sample assays indicated that SIX4 is upregulated in inflammatory bowel disease (IBD) and colorectal cancer (CRC) tissues compared to normal colorectal tissues. In a subsequent study, we found that SIX4, transcriptionally activated by the proinflammatory IL-6/STAT3 signal, binds to c-Jun to transcribe IL-6, thus forming a positive IL-6/STAT3/SIX4/c-Jun feedback loop, which further induces intestinal inflammation occurrence. In addition, elevated SIX4 also induces the expression of DeltaNp63, rather than wild-type p63, by binding to its promoter and thus facilitates the activation of tumor stemness signals, which ultimately leads to the formation of colorectal cancer. Our study first observes that activated SIX4 in inflammation induction drives the transformation of colorectal epithelium into inflammation and tumor, which demonstrates SIX4 as a significant therapeutic target in IBD and colitis-associated colorectal cancer (CAC) and CRC pathogenesis.
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Affiliation(s)
- Ziyan Zhang
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, 510315, Guangzhou, China
- Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 528406, Guangzhou, China
- Department of gynecology and obstetrics, The Third Affiliated Hospital, Southern Medical University, 510630, Guangzhou, China
| | - Huang Huang
- Nursing Department of Nanfang Hospital, Southern Medical University, 510516, Guangzhou, China
| | - Lanzhu Peng
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, 510315, Guangzhou, China
| | - Beixian Zhou
- The People's Hospital of Gaozhou, Gaozhou, 525200, China
| | - Huiling Yang
- School of Pharmacy, Guangdong Medical University, 523808, Dongguan, China
| | - Zibo Tang
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, 510315, Guangzhou, China
- Department of Radiation Oncology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, China
| | - Weiwei Yan
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, 510315, Guangzhou, China
| | - Weifeng Chen
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, 510315, Guangzhou, China
| | - Zhen Liu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, 510095, China
| | - Dayong Zheng
- Shunde Hospital of South Medical University, Foshan City, Guangdong, China
- Kashi first people's Hospital, 844099, Kashi, China
| | - Peng Shen
- Department of Oncology, Nanfang Hospital of Southern Medical University, 510515, Guangzhou, China
| | - Weiyi Fang
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, 510315, Guangzhou, China
- Department of gynecology and obstetrics, The Third Affiliated Hospital, Southern Medical University, 510630, Guangzhou, China
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Li J, Ji Y, Chen N, Dai L, Deng H. Colitis-associated carcinogenesis: crosstalk between tumors, immune cells and gut microbiota. Cell Biosci 2023; 13:194. [PMID: 37875976 PMCID: PMC10594787 DOI: 10.1186/s13578-023-01139-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 09/21/2023] [Indexed: 10/26/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide. One of the main causes of colorectal cancer is inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD). Intestinal epithelial cells (IECs), intestinal mesenchymal cells (IMCs), immune cells, and gut microbiota construct the main body of the colon and maintain colon homeostasis. In the development of colitis and colitis-associated carcinogenesis, the damage, disorder or excessive recruitment of different cells such as IECs, IMCs, immune cells and intestinal microbiota play different roles during these processes. This review aims to discuss the various roles of different cells and the crosstalk of these cells in transforming intestinal inflammation to cancer, which provides new therapeutic methods for chemotherapy, targeted therapy, immunotherapy and microbial therapy.
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Affiliation(s)
- Junshu Li
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Ke Yuan Road 4, No. 1 Gao Peng Street, Chengdu, 610041, China
| | - Yanhong Ji
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Ke Yuan Road 4, No. 1 Gao Peng Street, Chengdu, 610041, China
| | - Na Chen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Ke Yuan Road 4, No. 1 Gao Peng Street, Chengdu, 610041, China
| | - Lei Dai
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Ke Yuan Road 4, No. 1 Gao Peng Street, Chengdu, 610041, China.
| | - Hongxin Deng
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Ke Yuan Road 4, No. 1 Gao Peng Street, Chengdu, 610041, China.
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Xia Y, Zhang L, Ocansey DKW, Tu Q, Mao F, Sheng X. Role of glycolysis in inflammatory bowel disease and its associated colorectal cancer. Front Endocrinol (Lausanne) 2023; 14:1242991. [PMID: 37881499 PMCID: PMC10595037 DOI: 10.3389/fendo.2023.1242991] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 09/25/2023] [Indexed: 10/27/2023] Open
Abstract
Inflammatory bowel disease (IBD) has been referred to as the "green cancer," and its progression to colorectal cancer (CRC) poses a significant challenge for the medical community. A common factor in their development is glycolysis, a crucial metabolic mechanism of living organisms, which is also involved in other diseases. In IBD, glycolysis affects gastrointestinal components such as the intestinal microbiota, mucosal barrier function, and the immune system, including macrophages, dendritic cells, T cells, and neutrophils, while in CRC, it is linked to various pathways, such as phosphatidylinositol-3-kinase (PI3K)/AKT, AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and transcription factors such as p53, Hypoxia-inducible factor (HIF), and c-Myc. Thus, a comprehensive study of glycolysis is essential for a better understanding of the pathogenesis and therapeutic targets of both IBD and CRC. This paper reviews the role of glycolysis in diseases, particularly IBD and CRC, via its effects on the intestinal microbiota, immunity, barrier integrity, signaling pathways, transcription factors and some therapeutic strategies targeting glycolytic enzymes.
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Affiliation(s)
- Yuxuan Xia
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Li Zhang
- Nanjing Lishui People’s Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, Jiangsu, China
| | - Dickson Kofi Wiredu Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
- Directorate of University Health Services, University of Cape Coast, Cape Coast, Ghana
| | - Qiang Tu
- Clinical Laboratory, Nanjing Jiangning Hospital, Nanjing, Jiangsu, China
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Xiumei Sheng
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
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Mannick JB, Lamming DW. Targeting the biology of aging with mTOR inhibitors. NATURE AGING 2023; 3:642-660. [PMID: 37142830 PMCID: PMC10330278 DOI: 10.1038/s43587-023-00416-y] [Citation(s) in RCA: 139] [Impact Index Per Article: 69.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 04/07/2023] [Indexed: 05/06/2023]
Abstract
Inhibition of the protein kinase mechanistic target of rapamycin (mTOR) with the Food and Drug Administration (FDA)-approved therapeutic rapamycin promotes health and longevity in diverse model organisms. More recently, specific inhibition of mTORC1 to treat aging-related conditions has become the goal of basic and translational scientists, clinicians and biotechnology companies. Here, we review the effects of rapamycin on the longevity and survival of both wild-type mice and mouse models of human diseases. We discuss recent clinical trials that have explored whether existing mTOR inhibitors can safely prevent, delay or treat multiple diseases of aging. Finally, we discuss how new molecules may provide routes to the safer and more selective inhibition of mTOR complex 1 (mTORC1) in the decade ahead. We conclude by discussing what work remains to be done and the questions that will need to be addressed to make mTOR inhibitors part of the standard of care for diseases of aging.
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Affiliation(s)
| | - Dudley W Lamming
- Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
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Jangani M, Vuononvirta J, Yamani L, Ward E, Capasso M, Nadkarni S, Balkwill F, Marelli-Berg F. Loss of mTORC2-induced metabolic reprogramming in monocytes uncouples migration and maturation from production of proinflammatory mediators. J Leukoc Biol 2022; 111:967-980. [PMID: 34585416 DOI: 10.1002/jlb.1a0920-588r] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Monocyte migration to the sites of inflammation and maturation into macrophages are key steps for their immune effector function. Here, we show that mechanistic target of rapamycin complex 2 (mTORC2)-dependent Akt activation is instrumental for metabolic reprogramming at the early stages of macrophage-mediated immunity. Despite an increased production of proinflammatory mediators, monocytes lacking expression of the mTORC2 component Rictor fail to efficiently migrate to inflammatory sites and fully mature into macrophages, resulting in reduced inflammatory responses in vivo. The mTORC2-dependent phosphorylation of Akt is instrumental for the enhancement of glycolysis and mitochondrial respiration, required to sustain monocyte maturation and motility. These observations are discussed in the context of therapeutic strategies aimed at selective inhibition of mTORC2 activity.
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Affiliation(s)
- Maryam Jangani
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK
| | - Juho Vuononvirta
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK
| | - Lamya Yamani
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK
| | - Eleanor Ward
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK
| | - Melania Capasso
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK
- German Center for Neurodegenerative Diseases (DZNE) within the Helmholtz Association, Bonn, Germany
| | - Suchita Nadkarni
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK
| | - Frances Balkwill
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK
| | - Federica Marelli-Berg
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK
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Ramel E, Lillo S, Daher B, Fioleau M, Daubon T, Saleh M. The Metabolic Control of Myeloid Cells in the Tumor Microenvironment. Cells 2021; 10:cells10112960. [PMID: 34831183 PMCID: PMC8616208 DOI: 10.3390/cells10112960] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/23/2021] [Accepted: 10/26/2021] [Indexed: 12/23/2022] Open
Abstract
Myeloid cells are a key determinant of tumor progression and patient outcomes in a range of cancers and are therefore being actively pursued as targets of new immunotherapies. The recent use of high-dimensional single-cell approaches, e.g., mass cytometry and single-cell RNA-sequencing (scRNA-seq) has reinforced the predominance of myeloid cells in the tumor microenvironment and uncovered their phenotypic diversity in different cancers. The cancerous metabolic environment has emerged as a critical modulator of myeloid cell functions in anti-tumor immunity versus immune suppression and immune evasion. Here, we discuss mechanisms of immune-metabolic crosstalk in tumorigenesis, with a particular focus on the tumor-associated myeloid cell’s metabolic programs. We highlight the impact of several metabolic pathways on the pro-tumoral functions of tumor-associated macrophages and myeloid-derived suppressor cells and discuss the potential myeloid cell metabolic checkpoints for cancer immunotherapy, either as monotherapies or in combination with other immunotherapies.
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Affiliation(s)
- Eloise Ramel
- ImmunoConcEpT, CNRS, University of Bordeaux, UMR 5164, F-33000 Bordeaux, France; (E.R.); (S.L.); (M.F.)
| | - Sebastian Lillo
- ImmunoConcEpT, CNRS, University of Bordeaux, UMR 5164, F-33000 Bordeaux, France; (E.R.); (S.L.); (M.F.)
| | - Boutaina Daher
- Institut de Biochimie et Génétique Cellulaires (IBGC), CNRS, University of Bordeaux, UMR 5095, F-33000 Bordeaux, France; (B.D.); (T.D.)
| | - Marina Fioleau
- ImmunoConcEpT, CNRS, University of Bordeaux, UMR 5164, F-33000 Bordeaux, France; (E.R.); (S.L.); (M.F.)
| | - Thomas Daubon
- Institut de Biochimie et Génétique Cellulaires (IBGC), CNRS, University of Bordeaux, UMR 5095, F-33000 Bordeaux, France; (B.D.); (T.D.)
| | - Maya Saleh
- ImmunoConcEpT, CNRS, University of Bordeaux, UMR 5164, F-33000 Bordeaux, France; (E.R.); (S.L.); (M.F.)
- Department of Medicine, McGill University, Montreal, QC H3G 0B1, Canada
- Correspondence:
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10
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Braun C, Weichhart T. mTOR-dependent immunometabolism as Achilles' heel of anticancer therapy. Eur J Immunol 2021; 51:3161-3175. [PMID: 34648202 DOI: 10.1002/eji.202149270] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 07/07/2021] [Accepted: 10/06/2021] [Indexed: 12/14/2022]
Abstract
Immune cells are important constituents of the tumor microenvironment and essential in eradicating tumor cells during conventional therapies or novel immunotherapies. The mechanistic target of rapamycin (mTOR) signaling pathway senses the intra- and extracellular nutrient status, growth factor supply, and cell stress-related changes to coordinate cellular metabolism and activation dictating effector and memory functions in mainly all hematopoietic immune cells. In addition, the mTOR complex 1 (mTORC1) and mTORC2 are frequently deregulated and become activated in cancer cells to drive cell transformation, survival, neovascularization, and invasion. In this review, we provide an overview of the influence of mTOR complexes on immune and cancer cell function and metabolism. We discuss how mTOR inhibitors aiming to target cancer cells will influence immunometabolic cell functions participating either in antitumor responses or favoring tumor cell progression in individual immune cells. We suggest immunometabolism as the weak spot of anticancer therapy and propose to evaluate patients according to their predominant immune cell subtype in the cancer tissue. Advances in metabolic drug development that hold promise for more effective treatments in different types of cancer will have to consider their effects on the immune system.
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Affiliation(s)
- Clarissa Braun
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.,Clinical Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Weichhart
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
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11
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van Maldegem F, Valand K, Cole M, Patel H, Angelova M, Rana S, Colliver E, Enfield K, Bah N, Kelly G, Tsang VSK, Mugarza E, Moore C, Hobson P, Levi D, Molina-Arcas M, Swanton C, Downward J. Characterisation of tumour microenvironment remodelling following oncogene inhibition in preclinical studies with imaging mass cytometry. Nat Commun 2021; 12:5906. [PMID: 34625563 PMCID: PMC8501076 DOI: 10.1038/s41467-021-26214-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 09/20/2021] [Indexed: 01/23/2023] Open
Abstract
Mouse models are critical in pre-clinical studies of cancer therapy, allowing dissection of mechanisms through chemical and genetic manipulations that are not feasible in the clinical setting. In studies of the tumour microenvironment (TME), multiplexed imaging methods can provide a rich source of information. However, the application of such technologies in mouse tissues is still in its infancy. Here we present a workflow for studying the TME using imaging mass cytometry with a panel of 27 antibodies on frozen mouse tissues. We optimise and validate image segmentation strategies and automate the process in a Nextflow-based pipeline (imcyto) that is scalable and portable, allowing for parallelised segmentation of large multi-image datasets. With these methods we interrogate the remodelling of the TME induced by a KRAS G12C inhibitor in an immune competent mouse orthotopic lung cancer model, highlighting the infiltration and activation of antigen presenting cells and effector cells.
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Affiliation(s)
- Febe van Maldegem
- Oncogene Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081HZ, Amsterdam, The Netherlands.
| | - Karishma Valand
- Oncogene Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
| | - Megan Cole
- Oncogene Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
| | - Harshil Patel
- Bioinformatics and Biostatistics Science Technology Platform, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
| | - Mihaela Angelova
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
| | - Sareena Rana
- Oncogene Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
- Lung Cancer Group, Division of Molecular Pathology, Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK
| | - Emma Colliver
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
| | - Katey Enfield
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
| | - Nourdine Bah
- Bioinformatics and Biostatistics Science Technology Platform, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
| | - Gavin Kelly
- Bioinformatics and Biostatistics Science Technology Platform, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
| | - Victoria Siu Kwan Tsang
- Oncogene Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
| | - Edurne Mugarza
- Oncogene Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
| | - Christopher Moore
- Oncogene Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
| | - Philip Hobson
- Flow Cytometry Science Technology Platform, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
| | - Dina Levi
- Flow Cytometry Science Technology Platform, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
| | - Miriam Molina-Arcas
- Oncogene Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
| | - Charles Swanton
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6DD, UK
| | - Julian Downward
- Oncogene Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
- Lung Cancer Group, Division of Molecular Pathology, Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.
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12
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Chaudhary S, Pothuraju R, Rachagani S, Siddiqui JA, Atri P, Mallya K, Nasser MW, Sayed Z, Lyden ER, Smith L, Gupta SD, Ralhan R, Lakshmanan I, Jones DT, Ganti AK, Macha MA, Batra SK. Dual blockade of EGFR and CDK4/6 delays head and neck squamous cell carcinoma progression by inducing metabolic rewiring. Cancer Lett 2021; 510:79-92. [PMID: 33878394 PMCID: PMC8153085 DOI: 10.1016/j.canlet.2021.04.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 04/05/2021] [Accepted: 04/07/2021] [Indexed: 12/15/2022]
Abstract
Despite preclinical success, monotherapies targeting EGFR or cyclin D1-CDK4/6 in Head and Neck squamous cell carcinoma (HNSCC) have shown a limited clinical outcome. Here, we aimed to determine the combined effect of palbociclib (CDK4/6) and afatinib (panEGFR) inhibitors as an effective strategy to target HNSCC. Using TCGA-HNSCC co-expression analysis, we found that patients with high EGFR and cyclin D1 expression showed enrichment of gene clusters associated with cell-growth, glycolysis, and epithelial to mesenchymal transition processes. Phosphorylated S6 (p-S6), a downstream effector of EGFR and cyclin D1-CDK4/6 signalling, showed a progressive increase from normal oral tissues to leukoplakia and frank malignancy, and associated with poor outcome of the patients. This increased p-S6 expression was drastically reduced after combination treatment with afatinib and palbociclib in the cell lines and mouse models, suggesting its utiliy as a prognostic marker in HNSCC. Combination treatment also reduced the cell growth and induced cell senescence via increasing reactive oxygen species with concurrent ablation of glycolytic and tricarboxylic acid cycle intermediates. Finally, our findings in sub-cutaneous and genetically engineered mouse model (K14-CreERtam;LSL-KrasG12D/+;Trp53R172H/+) studies showed a significant reduction in the tumor growth and delayed tumor progression after combination treatment. This study collectively demonstrates that dual targeting may be a critical therapeutic strategy in blocking tumor progression via inducing metabolic alteration and warrants clinical evaluation.
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Affiliation(s)
- Sanjib Chaudhary
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Ramesh Pothuraju
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Jawed A Siddiqui
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Pranita Atri
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Kavita Mallya
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Mohd W Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Zafar Sayed
- Department of Otolaryngology-Head & Neck Surgery, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Elizabeth R Lyden
- Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Lynette Smith
- Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Siddhartha D Gupta
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, Delhi, 110029, India
| | - Ranju Ralhan
- Department of Otolaryngology-Head & Neck Surgery, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada
| | - Imayavaramban Lakshmanan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Dwight T Jones
- Department of Otolaryngology-Head & Neck Surgery, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Apar Kishor Ganti
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Division of Oncology-Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, 68105, USA.
| | - Muzafar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Awantipora, Jammu and Kashmir, 192122, India.
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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13
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Li M, Huang T, Li X, Shi Z, Sheng Y, Hu M, Song K. GDC-0575, a CHK1 Inhibitor, Impairs the Development of Colitis and Colitis-Associated Cancer by Inhibiting CCR2 + Macrophage Infiltration in Mice. Onco Targets Ther 2021; 14:2661-2672. [PMID: 33897258 PMCID: PMC8058335 DOI: 10.2147/ott.s297132] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 03/26/2021] [Indexed: 01/15/2023] Open
Abstract
Background Checkpoint kinase 1 (CHK1) plays an important role in DNA damage response and cell cycle progression. Thus, targeting CHK1 is an efficient strategy for cancer therapy. Purpose The present study aimed to investigate the potential therapeutic effects of GDC-0575, a CHK1-specific inhibitor, in colitis-associated cancer (CAC) and colitis. Methods We established a DSS-induced acute colitis model and an azoxymethane/dextran sodium sulfate (DSS)-induced CAC model using mice and tested the effect of GDC-0575 on them. Flow cytometry and immunofluorescence were employed to investigate the infiltration of immune cells, and inflammatory cytokine expression in the colon of mice with CAC or colitis was investigated using ELISA and qPCR. We also investigated the correlation between CHK1 and CCL2/CCR2 in human colorectal cancer (CRC) tissues. Results Administration of GDC-0575 significantly inhibited CHK1 expression in the colon and dramatically impaired the development of CAC and colitis in mice. Moreover, the inhibition of CHK1 expression resulted in efficient inhibition of infiltration by iNOS-positive macrophages, but had no significant effect on CD4 T cells, CD8 T cells, and myeloid-derived suppressor cells (MDSCs). Significant downregulation of TNF-α, IL-6, and IL-1β and dramatic upregulation of IL-10 were observed in the colons of both mice with CAC and colitis treated with GDC-0575. CCL2 expression was also downregulated by GDC-0575 in both mice with CAC and colitis; this was followed by the inhibition of CCR2+ macrophage infiltration in the colon. Furthermore, we report a positive correlation between CHK1 expression and CCL2/CCR2 expression in the malignant tissues of patients with CRC. Conclusion Taken together, we infer that GDC-0575 impairs the development of CAC and colitis by regulating cytokine expression and inhibiting CCR2+ macrophage infiltration in mice colon.
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Affiliation(s)
- Min Li
- Department of Pharmacy, The First Affiliated Hospital of Jishou University, Jishou, Hunan, 416000, People's Republic of China
| | - Tianqing Huang
- Department of Neurology, The First Affiliated Hospital of Jishou University, Jishou, Hunan, 416000, People's Republic of China
| | - Xiaolan Li
- Department of Hematology, The First Affiliated Hospital of Jishou University, Jishou, Hunan, 416000, People's Republic of China
| | - Zhiwei Shi
- Department of Hematology, The First Affiliated Hospital of Jishou University, Jishou, Hunan, 416000, People's Republic of China
| | - Yue Sheng
- Department of Pediatrics, The First Affiliated Hospital of Jishou University, Jishou, Hunan, 416000, People's Republic of China
| | - Mimi Hu
- Department of Hematology, The First Affiliated Hospital of Jishou University, Jishou, Hunan, 416000, People's Republic of China
| | - Kui Song
- Department of Hematology, The First Affiliated Hospital of Jishou University, Jishou, Hunan, 416000, People's Republic of China
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14
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Gmeiner WH. Recent Advances in Our Knowledge of mCRC Tumor Biology and Genetics: A Focus on Targeted Therapy Development. Onco Targets Ther 2021; 14:2121-2130. [PMID: 33790575 PMCID: PMC8007558 DOI: 10.2147/ott.s242224] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 03/11/2021] [Indexed: 12/20/2022] Open
Abstract
Metastatic colorectal cancer (mCRC) remains a highly lethal malignancy although considerable progress has resulted from characterizing molecular alterations such as RAS mutation status and extent of microsatellite instability (MSI) to guide optimal use of available therapies. The availability of gene expression profiling, next generation sequencing technologies, proteomics analysis and other technologies provides high resolution information on individual tumors, including metastatic lesions to better define intra-tumor and inter-tumor heterogeneity. Recent literature applying this information to further customize personalized therapies is reviewed. Current biomarker-based stratification used to select optimal therapy that is personalized to the mutation profile of individual tumors is described. Recent literature using whole exome sequencing of metastatic lesions and primary CRC tumors and other advanced technologies to more fully elucidate the tumor biology specific to mCRC sub-types and to develop more precise therapies that improve outcomes is also reviewed.
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Affiliation(s)
- William H Gmeiner
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA
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15
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Ahn R, Ursini-Siegel J. Clinical Potential of Kinase Inhibitors in Combination with Immune Checkpoint Inhibitors for the Treatment of Solid Tumors. Int J Mol Sci 2021; 22:ijms22052608. [PMID: 33807608 PMCID: PMC7961781 DOI: 10.3390/ijms22052608] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 02/28/2021] [Accepted: 03/03/2021] [Indexed: 12/11/2022] Open
Abstract
Oncogenic kinases contribute to immunosuppression and modulate the tumor microenvironment in solid tumors. Increasing evidence supports the fundamental role of oncogenic kinase signaling networks in coordinating immunosuppressive tumor microenvironments. This has led to numerous studies examining the efficacy of kinase inhibitors in inducing anti-tumor immune responses by increasing tumor immunogenicity. Kinase inhibitors are the second most common FDA-approved group of drugs that are deployed for cancer treatment. With few exceptions, they inevitably lead to intrinsic and/or acquired resistance, particularly in patients with metastatic disease when used as a monotherapy. On the other hand, cancer immunotherapies, including immune checkpoint inhibitors, have revolutionized cancer treatment for malignancies such as melanoma and lung cancer. However, key hurdles remain to successfully incorporate such therapies in the treatment of other solid cancers. Here, we review the recent literature on oncogenic kinases that regulate tumor immunogenicity, immune suppression, and anti-tumor immunity. Furthermore, we discuss current efforts in clinical trials that combine kinase inhibitors and immune checkpoint inhibitors to treat breast cancer and other solid tumors.
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Affiliation(s)
- Ryuhjin Ahn
- Department of Biological Engineering, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA;
| | - Josie Ursini-Siegel
- Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC H3T 1E2, Canada
- Department of Experimental Medicine, McGill University, Montréal, QC H3A 0G4, Canada
- Department of Oncology, McGill University, 546 Pine Avenue West, Montréal, QC H2W 1S6, Canada
- Correspondence: ; Tel.: +514-340-8222 (ext. 26557); Fax: +514-340-7502
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16
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Klement JD, Poschel DB, Lu C, Merting AD, Yang D, Redd PS, Liu K. Osteopontin Blockade Immunotherapy Increases Cytotoxic T Lymphocyte Lytic Activity and Suppresses Colon Tumor Progression. Cancers (Basel) 2021; 13:cancers13051006. [PMID: 33670921 PMCID: PMC7957528 DOI: 10.3390/cancers13051006] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/18/2021] [Accepted: 02/19/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary Despite the breakthrough in human cancer immunotherapy, colorectal cancer, except for the small subset of microsatellite instable colorectal cancer (MSI, ~4% total cases), is one of the few human cancers that does not respond to current immune checkpoint inhibitor (ICI) immunotherapy. CTLs are present in both MSI and microsatellite stable (MSS) human colon carcinoma, suggesting that PD-L1-independent mechanisms may exist and suppress CTL activation in the colon tumor microenvironment. We determined that osteopontin (OPN) inhibits tumor-specific cytotoxic T lymphocyte (CTL) lytic activity to promote colon tumor growth in vivo. Accordingly, OPN blockade immunotherapy using OPN neutralization monoclonal antibodies 100D3 and 103D6 suppressed colon tumor growth in vivo. Our findings indicate that 100D3 and 103D6 has the potential to be further developed for colorectal cancer immunotherapy. Abstract Human colorectal cancers are mostly microsatellite-stable with no response to anti-PD-1 blockade immunotherapy, necessitating the development of a new immunotherapy. Osteopontin (OPN) is elevated in human colorectal cancer and may function as an immune checkpoint. We aimed at elucidating the mechanism of action of OPN and determining the efficacy of OPN blockade immunotherapy in suppression of colon cancer. We report here that OPN is primarily expressed in tumor cells, myeloid cells, and innate lymphoid cells in human colorectal carcinoma. Spp1 knock out mice exhibit a high incidence and fast growth rate of carcinogen-induced tumors. Knocking out Spp1 in colon tumor cells increased tumor-specific CTL cytotoxicity in vitro and resulted in decreased tumor growth in vivo. The OPN protein level is elevated in the peripheral blood of tumor-bearing mice. We developed four OPN neutralization monoclonal antibodies based on their efficacy in blocking OPN inhibition of T cell activation. OPN clones 100D3 and 103D6 increased the efficacy of tumor-specific CTLs in killing colon tumor cells in vitro and suppressed colon tumor growth in tumor-bearing mice in vivo. Our data indicate that OPN blockade immunotherapy with 100D3 and 103D6 has great potential to be further developed for colorectal cancer immunotherapy and for rendering a colorectal cancer response to anti-PD-1 immunotherapy.
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Affiliation(s)
- John D. Klement
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; (J.D.K.); (D.B.P.); (A.D.M.); (D.Y.); (P.S.R.)
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
- Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Dakota B. Poschel
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; (J.D.K.); (D.B.P.); (A.D.M.); (D.Y.); (P.S.R.)
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
- Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Chunwan Lu
- School of Life Sciences, Tianjin University, Tianjin 300072, China;
| | - Alyssa D. Merting
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; (J.D.K.); (D.B.P.); (A.D.M.); (D.Y.); (P.S.R.)
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
- Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Dafeng Yang
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; (J.D.K.); (D.B.P.); (A.D.M.); (D.Y.); (P.S.R.)
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
- Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Priscilla S. Redd
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; (J.D.K.); (D.B.P.); (A.D.M.); (D.Y.); (P.S.R.)
- Chemedimmune Inc., Augusta, GA 30912, USA
| | - Kebin Liu
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; (J.D.K.); (D.B.P.); (A.D.M.); (D.Y.); (P.S.R.)
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
- Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
- Correspondence: ; Tel.: +1-706-721-9483
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17
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Larionova I, Tuguzbaeva G, Ponomaryova A, Stakheyeva M, Cherdyntseva N, Pavlov V, Choinzonov E, Kzhyshkowska J. Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian and Prostate Cancers. Front Oncol 2020; 10:566511. [PMID: 33194645 PMCID: PMC7642726 DOI: 10.3389/fonc.2020.566511] [Citation(s) in RCA: 261] [Impact Index Per Article: 52.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 09/21/2020] [Indexed: 12/11/2022] Open
Abstract
Tumor-associated macrophages (TAMs) are major innate immune cells that constitute up to 50% of the cell mass of human tumors. TAMs are highly heterogeneous cells that originate from resident tissue-specific macrophages and from newly recruited monocytes. TAMs' variability strongly depends on cancer type, stage, and intratumor heterogeneity. Majority of TAMs are programmed by tumor microenvironment to support primary tumor growth and metastatic spread. However, TAMs can also restrict tumor growth and metastasis. In this review, we summarized the knowledge about the role of TAMs in tumor growth, metastasis and in the response to cancer therapy in patients with five aggressive types of cancer: breast, colorectal, lung, ovarian, and prostate cancers that are frequently metastasize into distant organs resulting in high mortality of the patients. Two major TAM parameters are applied for the evaluation of TAM correlation with the cancer progression: total amount of TAMs and specific phenotype of TAMs identified by functional biomarkers. We summarized the data generated in the wide range of international patient cohorts on the correlation of TAMs with clinical and pathological parameters of tumor progression including lymphatic and hematogenous metastasis, recurrence, survival, therapy efficiency. We described currently available biomarkers for TAMs that can be measured in patients' samples (tumor tissue and blood). CD68 is the major biomarker for the quantification of total TAM amounts, while transmembrane receptors (stabilin-1, CD163, CD206, CD204, MARCO) and secreted chitinase-like proteins (YKL-39, YKL-40) are used as biomarkers for the functional TAM polarization. We also considered that specific role of TAMs in tumor progression can depend on the localization in the intratumoral compartments. We have made the conclusion for the role of TAMs in primary tumor growth, metastasis, and therapy sensitivity for breast, colorectal, lung, ovarian, and prostate cancers. In contrast to other cancer types, majority of clinical studies indicate that TAMs in colorectal cancer have protective role for the patient and interfere with primary tumor growth and metastasis. The accumulated data are essential for using TAMs as biomarkers and therapeutic targets to develop cancer-specific immunotherapy and to design efficient combinations of traditional therapy and new immunomodulatory approaches.
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Affiliation(s)
- Irina Larionova
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk, Russia
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Gulnara Tuguzbaeva
- Department of Pathophysiology, Bashkir State Medical University, Ufa, Russia
| | - Anastasia Ponomaryova
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Marina Stakheyeva
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Nadezhda Cherdyntseva
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk, Russia
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Valentin Pavlov
- Department of Urology, Bashkir State Medical University, Ufa, Russia
| | - Evgeniy Choinzonov
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Julia Kzhyshkowska
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk, Russia
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- German Red Cross Blood Service Baden-Württemberg—Hessen, Mannheim, Germany
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18
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Fritsch SD, Weichhart T. Metabolic and immunologic control of intestinal cell function by mTOR. Int Immunol 2020; 32:455-465. [PMID: 32140726 PMCID: PMC7617511 DOI: 10.1093/intimm/dxaa015] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 02/28/2020] [Indexed: 02/06/2023] Open
Abstract
The intestinal epithelium is one of the most quickly dividing tissues in our body, combining the absorptive advantages of a single layer with the protection of a constantly renewing barrier. It is continuously exposed to nutrients and commensal bacteria as well as microbial and host-derived metabolites, but also to hazards such as pathogenic bacteria and toxins. These environmental cues are sensed by the mucosa and a vast repertory of immune cells, especially macrophages. A disruption of intestinal homeostasis in terms of barrier interruption can lead to inflammatory bowel diseases and colorectal cancer, and macrophages have an important role in restoring epithelial function following injury. The mammalian/mechanistic target of rapamycin (mTOR) signalling pathway senses environmental cues and integrates metabolic responses. It has emerged as an important regulator of intestinal functions in homeostasis and disease. In this review, we are going to discuss intestinal mTOR signalling and metabolic regulation in different intestinal cell populations with a special focus on immune cells and their actions on intestinal function.
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Affiliation(s)
- Stephanie D Fritsch
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Währinger Straße, Vienna, Austria
| | - Thomas Weichhart
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Währinger Straße, Vienna, Austria
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19
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Jin J, Zhao Q. Emerging role of mTOR in tumor immune contexture: Impact on chemokine-related immune cells migration. Theranostics 2020; 10:6231-6244. [PMID: 32483450 PMCID: PMC7255024 DOI: 10.7150/thno.45219] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Accepted: 04/17/2020] [Indexed: 12/27/2022] Open
Abstract
During the last few decades, cell-based anti-tumor immunotherapy emerged and it has provided us with a large amount of knowledge. Upon chemokines recognition, immune cells undergo rapid trafficking and activation in disease milieu, with immune cells chemotaxis being accompanied by activation of diverse intercellular signal transduction pathways. The outcome of chemokines-mediated immune cells chemotaxis interacts with the cue of mammalian target of rapamycin (mTOR) in the tumor microenvironment (TME). Indeed, the mTOR cascade in immune cells involves migration and infiltration. In this review, we summarize the available mTOR-related chemokines, as well as the characterized upstream regulators and downstream targets in immune cells chemotaxis and assign potential underlying mechanisms in each evaluated chemokine. Specifically, we focus on the involvement of mTOR in chemokine-mediated immune related cells in the balance between tumor immunity and malignancy.
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Affiliation(s)
- Jing Jin
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Qijie Zhao
- Laboratory of Molecular Pharmacology, Southwest Medical University, Luzhou, 646000, Sichuan, PR China
- Department of Pathophysiology, College of Basic Medical Science, Southwest Medical University, Luzhou, 646000, Sichuan, PR China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, Sichuan, PR China
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