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Kzhyshkowska J, Shen J, Larionova I. Targeting of TAMs: can we be more clever than cancer cells? Cell Mol Immunol 2024; 21:1376-1409. [PMID: 39516356 PMCID: PMC11607358 DOI: 10.1038/s41423-024-01232-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 10/12/2024] [Indexed: 11/16/2024] Open
Abstract
АBSTRACT: With increasing incidence and geography, cancer is one of the leading causes of death, reduced quality of life and disability worldwide. Principal progress in the development of new anticancer therapies, in improving the efficiency of immunotherapeutic tools, and in the personification of conventional therapies needs to consider cancer-specific and patient-specific programming of innate immunity. Intratumoral TAMs and their precursors, resident macrophages and monocytes, are principal regulators of tumor progression and therapy resistance. Our review summarizes the accumulated evidence for the subpopulations of TAMs and their increasing number of biomarkers, indicating their predictive value for the clinical parameters of carcinogenesis and therapy resistance, with a focus on solid cancers of non-infectious etiology. We present the state-of-the-art knowledge about the tumor-supporting functions of TAMs at all stages of tumor progression and highlight biomarkers, recently identified by single-cell and spatial analytical methods, that discriminate between tumor-promoting and tumor-inhibiting TAMs, where both subtypes express a combination of prototype M1 and M2 genes. Our review focuses on novel mechanisms involved in the crosstalk among epigenetic, signaling, transcriptional and metabolic pathways in TAMs. Particular attention has been given to the recently identified link between cancer cell metabolism and the epigenetic programming of TAMs by histone lactylation, which can be responsible for the unlimited protumoral programming of TAMs. Finally, we explain how TAMs interfere with currently used anticancer therapeutics and summarize the most advanced data from clinical trials, which we divide into four categories: inhibition of TAM survival and differentiation, inhibition of monocyte/TAM recruitment into tumors, functional reprogramming of TAMs, and genetic enhancement of macrophages.
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Affiliation(s)
- Julia Kzhyshkowska
- Department of Innate Immunity and Tolerance, Institute of Transfusion Medicine and Immunology, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer, 1-3, 68167, Mannheim, Germany.
- German Red Cross Blood Service Baden-Württemberg - Hessen, Friedrich-Ebert Str. 107, 68167, Mannheim, Germany.
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050, Lenina av.36, Tomsk, Russia.
- Bashkir State Medical University of the Ministry of Health of Russia, 450000, Teatralnaya Street, 2a, Ufa, Russia.
| | - Jiaxin Shen
- Department of Innate Immunity and Tolerance, Institute of Transfusion Medicine and Immunology, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer, 1-3, 68167, Mannheim, Germany
- Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Irina Larionova
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050, Lenina av.36, Tomsk, Russia
- Bashkir State Medical University of the Ministry of Health of Russia, 450000, Teatralnaya Street, 2a, Ufa, Russia
- Laboratory of Molecular Therapy of Cancer, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009, Kooperativnyi st, Tomsk, Russia
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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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Huang R, Kang T, Chen S. The role of tumor-associated macrophages in tumor immune evasion. J Cancer Res Clin Oncol 2024; 150:238. [PMID: 38713256 PMCID: PMC11076352 DOI: 10.1007/s00432-024-05777-4] [Citation(s) in RCA: 45] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 05/03/2024] [Indexed: 05/08/2024]
Abstract
BACKGROUND Tumor growth is closely linked to the activities of various cells in the tumor microenvironment (TME), particularly immune cells. During tumor progression, circulating monocytes and macrophages are recruited, altering the TME and accelerating growth. These macrophages adjust their functions in response to signals from tumor and stromal cells. Tumor-associated macrophages (TAMs), similar to M2 macrophages, are key regulators in the TME. METHODS We review the origins, characteristics, and functions of TAMs within the TME. This analysis includes the mechanisms through which TAMs facilitate immune evasion and promote tumor metastasis. Additionally, we explore potential therapeutic strategies that target TAMs. RESULTS TAMs are instrumental in mediating tumor immune evasion and malignant behaviors. They release cytokines that inhibit effector immune cells and attract additional immunosuppressive cells to the TME. TAMs primarily target effector T cells, inducing exhaustion directly, influencing activity indirectly through cellular interactions, or suppressing through immune checkpoints. Additionally, TAMs are directly involved in tumor proliferation, angiogenesis, invasion, and metastasis. Developing innovative tumor-targeted therapies and immunotherapeutic strategies is currently a promising focus in oncology. Given the pivotal role of TAMs in immune evasion, several therapeutic approaches have been devised to target them. These include leveraging epigenetics, metabolic reprogramming, and cellular engineering to repolarize TAMs, inhibiting their recruitment and activity, and using TAMs as drug delivery vehicles. Although some of these strategies remain distant from clinical application, we believe that future therapies targeting TAMs will offer significant benefits to cancer patients.
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Affiliation(s)
- Ruizhe Huang
- Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Ting Kang
- Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Siyu Chen
- Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
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Wang P, Jie Y, Yao L, Sun YM, Jiang DP, Zhang SQ, Wang XY, Fan Y. Cells in the liver microenvironment regulate the process of liver metastasis. Cell Biochem Funct 2024; 42:e3969. [PMID: 38459746 DOI: 10.1002/cbf.3969] [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: 10/05/2023] [Revised: 01/31/2024] [Accepted: 02/26/2024] [Indexed: 03/10/2024]
Abstract
The research of liver metastasis is a developing field. The ability of tumor cells to invade the liver depends on the complicated interactions between metastatic cells and local subpopulations in the liver (including Kupffer cells, hepatic stellate cells, liver sinusoidal endothelial cells, and immune-related cells). These interactions are mainly mediated by intercellular adhesion and the release of cytokines. Cell populations in the liver microenvironment can play a dual role in the progression of liver metastasis through different mechanisms. At the same time, we can see the participation of liver parenchymal cells and nonparenchymal cells in the process of liver metastasis of different tumors. Therefore, the purpose of this article is to summarize the relationship between cellular components of liver microenvironment and metastasis and emphasize the importance of different cells in the occurrence or potential regression of liver metastasis.
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Affiliation(s)
- Pei Wang
- Cancer Institute, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yu Jie
- Cancer Institute, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Lin Yao
- Cancer Institute, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yi-Meng Sun
- Cancer Institute, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Da-Peng Jiang
- Cancer Institute, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Shi-Qi Zhang
- Department of Gastroenterology, The Affiliated Suqian First People's Hospital of Xuzhou Medical University, Suqian, Jiangsu, China
| | - Xiao-Yan Wang
- Department of Gastroenterology, The Affiliated Suqian First People's Hospital of Xuzhou Medical University, Suqian, Jiangsu, China
| | - Yu Fan
- Cancer Institute, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
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Karjula T, Elomaa H, Väyrynen SA, Kuopio T, Ahtiainen M, Mustonen O, Puro I, Niskakangas A, Mecklin JP, Böhm J, Wirta EV, Seppälä TT, Sihvo E, Yannopoulos F, Helminen O, Väyrynen JP. Multiplexed analysis of macrophage polarisation in pulmonary metastases of microsatellite stable colorectal cancer. Cancer Immunol Immunother 2024; 73:59. [PMID: 38386105 PMCID: PMC10884151 DOI: 10.1007/s00262-024-03646-0] [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: 11/25/2023] [Accepted: 01/29/2024] [Indexed: 02/23/2024]
Abstract
Tumour-associated macrophages (TAMs) express a continuum of phenotypes ranging from an anti-tumoural M1-like phenotype to a pro-tumoural M2-like phenotype. During cancer progression, TAMs may shift to a more M2-like polarisation state, but the role of TAMs in CRC metastases is unclear. We conducted a comprehensive spatial and prognostic analysis of TAMs in CRC pulmonary metastases and corresponding primary tumours using multiplexed immunohistochemistry and machine learning-based image analysis. We obtained data from 106 resected pulmonary metastases and 74 corresponding primary tumours. TAMs in the resected pulmonary metastases were located closer to the cancer cells and presented a more M2-like polarised state in comparison to the primary tumours. Higher stromal M2-like macrophage densities in the invasive margin of pulmonary metastases were associated with worse 5-year overall survival (HR 3.19, 95% CI 1.35-7.55, p = 0.008). The results of this study highlight the value of multiplexed analysis of macrophage polarisation in cancer metastases and might have clinical implications in future cancer therapy.
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Affiliation(s)
- Topias Karjula
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
| | - Hanna Elomaa
- Department of Biological and Environmental Science, University of Jyväskylä, 40014, Jyväskylä, Finland
- Department of Education and Research, Hospital Nova of Central Finland, Well Being Services County of Central Finland, 40620, Jyväskylä, Finland
| | - Sara A Väyrynen
- Department of Internal Medicine, Oulu University Hospital, Oulu, Finland
| | - Teijo Kuopio
- Department of Biological and Environmental Science, University of Jyväskylä, 40014, Jyväskylä, Finland
- Department of Pathology, Hospital Nova of Central Finland, Well Being Services County of Central Finland, 40620, Jyväskylä, Finland
| | - Maarit Ahtiainen
- Department of Pathology, Hospital Nova of Central Finland, Well Being Services County of Central Finland, 40620, Jyväskylä, Finland
| | - Olli Mustonen
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Iiris Puro
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Anne Niskakangas
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Jukka-Pekka Mecklin
- Department of Education and Research, Hospital Nova of Central Finland, Well Being Services County of Central Finland, 40620, Jyväskylä, Finland
- Faculty of Sport and Health Sciences, University of Jyväskylä, 40014, Jyväskylä, Finland
| | - Jan Böhm
- Department of Pathology, Hospital Nova of Central Finland, Well Being Services County of Central Finland, 40620, Jyväskylä, Finland
| | - Erkki-Ville Wirta
- Faculty of Medicine and Health Technology, Tampere University and TAYS Cancer Center, Tampere University Hospital, 33520, Tampere, Finland
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital and TAYS Cancer Centre, 33520, Tampere, Finland
| | - Toni T Seppälä
- Department of Gastrointestinal Surgery, Helsinki University Central Hospital, University of Helsinki, 00290, Helsinki, Finland
- Applied Tumor Genomics, Research Program Unit, University of Helsinki, 00290, Helsinki, Finland
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital and TAYS Cancer Centre, 33520, Tampere, Finland
| | - Eero Sihvo
- Central Hospital of Central Finland, 40014, Jyväskylä, Finland
| | - Fredrik Yannopoulos
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
- Department of Cardiothoracic Surgery, Oulu University Hospital, Oulu, Finland
| | - Olli Helminen
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Juha P Väyrynen
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
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Egidi MJ, Krug S, Haybaeck J, Michl P, Griesmann H. Anti-angiogenic therapy using the multi-tyrosine kinase inhibitor Regorafenib enhances tumor progression in a transgenic mouse model of ß-cell carcinogenesis. Br J Cancer 2023; 129:1225-1237. [PMID: 37620408 PMCID: PMC10575939 DOI: 10.1038/s41416-023-02389-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 07/12/2023] [Accepted: 07/31/2023] [Indexed: 08/26/2023] Open
Abstract
BACKGROUND Pancreatic neuroendocrine tumors (PNETs) represent a distinct hypervascularized tumor entity, often diagnosed at metastatic stage. Therapeutic efficacy of anti-angiogenic multi-kinase inhibitors is frequently limited by primary or acquired resistance in vivo. This study aimed to characterize the molecular mode of action as well as resistance mechanisms to the anti-angiogenic multi-tyrosine kinase inhibitor (TKI) Regorafenib in vitro and in vivo. METHODS In vitro, human and murine pancreatic neuroendocrine cell lines were comparatively treated with Regorafenib and other TKIs clinically used in PNETs. Effects on cell viability and proliferation were analyzed. In vivo, transgenic RIP1Tag2 mice were treated with Regorafenib at two different time periods during carcinogenesis and its impact on angiogenesis and tumor progression was evaluated. RESULTS Compared to the established TKI therapies with Sunitinib and Everolimus, Regorafenib showed the strongest effects on cell viability and proliferation in vitro, but was unable to induce apoptosis. Unexpectedly and in contrast to these in vitro findings, Regorafenib enhanced proliferation during early tumor development in RIP1Tag2 mice and had no significant effect in late tumor progression. In addition, invasiveness was increased at both time points. Mechanistically, we could identify an upregulation of the pro-survival protein Bcl-2, the induction of the COX2-PGE2-pathway as well as the infiltration of CSF1R positive immune cells into the tumors as potential resistance mechanisms following Regorafenib treatment. DISCUSSION Our data identify important tumor cell-autonomous and stroma-dependent mechanisms of resistance to antiangiogenic therapies.
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Affiliation(s)
- Maren Juliane Egidi
- Clinic for Internal Medicine I, Martin-Luther University Halle/Wittenberg, Ernst-Grube-Straße 40, D 06120, Halle, Germany
| | - Sebastian Krug
- Clinic for Internal Medicine I, Martin-Luther University Halle/Wittenberg, Ernst-Grube-Straße 40, D 06120, Halle, Germany
- Department of Internal Medicine IV, Heidelberg University Hospital, Heidelberg, Germany
| | - Johannes Haybaeck
- Department of Pathology, Neuropathology, and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria
- Diagnostic & Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Patrick Michl
- Clinic for Internal Medicine I, Martin-Luther University Halle/Wittenberg, Ernst-Grube-Straße 40, D 06120, Halle, Germany.
- Department of Internal Medicine IV, Heidelberg University Hospital, Heidelberg, Germany.
| | - Heidi Griesmann
- Clinic for Internal Medicine I, Martin-Luther University Halle/Wittenberg, Ernst-Grube-Straße 40, D 06120, Halle, Germany
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Guglietta S, Krieg C. Phenotypic and functional heterogeneity of monocytes in health and cancer in the era of high dimensional technologies. Blood Rev 2023; 58:101012. [PMID: 36114066 DOI: 10.1016/j.blre.2022.101012] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 08/16/2022] [Accepted: 08/18/2022] [Indexed: 11/23/2022]
Abstract
Monocytes have been traditionally classified in three discrete subsets, which can participate in the immune responses as effector cells or as precursors of myeloid-derived cells in circulation and tissues. However, recent advances in single-cell omics have revealed unprecedented phenotypic and functional heterogeneity that goes well beyond the three conventional monocytic subsets and propose a more fluid differentiation model. This novel concept does not only apply to the monocytes in circulation but also at the tissue site. Consequently, the binary model proposed for differentiating monocyte into M1 and M2 macrophages has been recently challenged by a spectrum model that more realistically mirrors the heterogeneous cues in inflammatory conditions. This review describes the latest results on the high dimensional characterization of monocytes and monocyte-derived myeloid cells in steady state and cancer. We discuss how environmental cues and monocyte-intrinsic properties may affect their differentiation toward specific functional and phenotypic subsets, the causes of monocyte expansion and reduction in cancer, their metabolic requirements, and the potential effect on tumor immunity.
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Affiliation(s)
- Silvia Guglietta
- Hollings Cancer Center, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Regenerative Medicine & Cell Biology, Medical University of South Carolina (MUSC), 173 Ashley Avenue, CRI609, Charleston, SC 29425, USA.
| | - Carsten Krieg
- Department of Pathology & Laboratory Medicine, Medical University of South Carolina (MUSC), 68 President Street, BE415, Charleston, SC 29425, USA; Hollings Cancer Center, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
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Deng S, Zhu Q, Chen H, Xiao T, Zhu Y, Gao J, Li Q, Gao Y. Screening of prognosis-related Immune cells and prognostic predictors in Colorectal Cancer Patients. BMC Cancer 2023; 23:195. [PMID: 36859111 PMCID: PMC9976376 DOI: 10.1186/s12885-023-10667-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 02/21/2023] [Indexed: 03/03/2023] Open
Abstract
OBJECTIVE To accurately screen potential immune cells that can predict the survival of colorectal cancer (CRC) patients and identify related prognostic predictors. METHODS The sample data of CRC patients were downloaded from the GEO database as a training set to establish a prognosis-scoring model and screen prognosis-related immune cells. The sample data of CRC patients from the TCGA database were used as the validation set. Simultaneously, cancer tissue samples from 116 patients with CRC diagnosed pathologically in Shanghai Dongfang Hospital were collected to analyze the relationship of prognosis-related immune cells with patients' survival, and clinical and pathological parameters, and to screen prognostic predictors. RESULTS Prognosis-related immune cells screened from GEO and TCGA databases mainly included Follicular Helper T cells (Tfh), Monocytes and M2 Macrophages. In the training set, the 2,000- and 4,000-day survival rates were 48.3% and 10.7% in the low-risk group (N = 234), and 42.1% and 7.5% in the high-risk group (N = 214), respectively. In the validation set, the 2,000- and 4,000-day survival rates were 34.8% and 8.6% in the low-risk group (N = 187), and 28.9% and 6.1% in the high-risk group (N = 246), respectively. The prognosis of patients in the high-risk group was worse than that in the low-risk group (P < 0.05). Furthermore, the screened primary prognostic predictors were CD163 and CD4 + CXCR5. CD163 protein expression was distributed in Monocytes and M2 Macrophages. The 1,000- and 2,000-day survival rates were 56.1% and 7.0% in the CD163 low-expression group, and 40.7% and 1.7% in the high-expression group (N = 214), respectively, showing a worse prognosis in the high-expression group than that in the low-expression group. Meanwhile, the immune marker CD4 + CXCR5 could identify Tfh. The 1,000- and 2,000-day survival rates were 63.9% and 5.6% in the CD4 + CXCR5 high-expression group, and 33.3% and 2.8% in the low-expression group (N = 214), respectively, with a better prognosis in the high-expression group than that in the low-expression group. CONCLUSION Prognostic-related immune cells of CRC mainly include Tfh cells, Monocytes and M2 Macrophages. Monocytes and M2 Macrophages correlate negatively, while Tfh cells correlate positively with the prognosis of CRC patients. Immune markers CD163 and CD4 + CXCR5 can be considered as the prognostic predictors of CRC with clinical value of the application.
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Affiliation(s)
- Shuangshuang Deng
- Department of Pathology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Qiping Zhu
- Department of Pathology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Hongyan Chen
- Department of Neurology, Luodian Hospital, Baoshan District, Shanghai, 201908, China
| | - Tianyu Xiao
- Department of Pathology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Yinshen Zhu
- Department of Pathology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Jinli Gao
- Department of Pathology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Qing Li
- Department of Pathology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Yong Gao
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
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Huang Z, Li B, Qin H, Mo X. Invasion characteristics and clinical significance of tumor-associated macrophages in gastrointestinal Krukenberg tumors. Front Oncol 2023; 13:1006183. [PMID: 36910657 PMCID: PMC9999382 DOI: 10.3389/fonc.2023.1006183] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 02/06/2023] [Indexed: 03/14/2023] Open
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) have been used as potential drug targets in preclinical research and clinical trials of various cancers. However, their distribution in Krukenberg tumors (KTs) remains unclear. We investigated the expression and prognostic value of TAMs in patients with gastrointestinal cancer with KTs. METHODS The infiltration of various types of TAMs was detected in surgical tissues of 35 patients with KTs using immunohistochemical staining. The level of infiltration of TAMs in tumor nests (TN), tumor stroma (TS), and invasive margin (IM) areas was evaluated. The Kaplan-Meier method and univariate/multivariate Cox regression risk models were used to analyze the relationship between the degree of TAMs invasion and overall survival (OS) and progression-free survival (PFS). RESULTS The distribution of TAMs exhibited spatial heterogeneity between TN, TS, and IM regions in primary tumor (PT) and KT tissues. TAMs infiltrated in the TN had greater prognostic value and were barely influenced by preoperative neoadjuvant therapy, despite similar grades of invasion in PT and KT tissues. Moreover, the number of CD68+ TAMs in TN of KT tissues was an independent risk factor affecting patient OS, whereas tumor resection scope might be an independent risk factor affecting patient PFS. CONCLUSIONS In view of the close relationship between TAMs, the tumor microenvironment and patient prognosis, targeting TAMs combined with chemotherapy is expected to become a new approach for the treatment of patients with KTs.
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Affiliation(s)
| | | | - Haiquan Qin
- Guangxi Clinical Research Center for Colorectal Cancer, Division of Colorectal & Anal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xianwei Mo
- *Correspondence: Haiquan Qin, ; Xianwei Mo,
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10
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Sullivan KM, Jiang X, Guha P, Lausted C, Carter JA, Hsu C, Labadie KP, Kohli K, Kenerson HL, Daniel SK, Yan X, Meng C, Abbasi A, Chan M, Seo YD, Park JO, Crispe IN, Yeung RS, Kim TS, Gujral TS, Tian Q, Katz SC, Pillarisetty VG. Blockade of interleukin 10 potentiates antitumour immune function in human colorectal cancer liver metastases. Gut 2023; 72:325-337. [PMID: 35705369 PMCID: PMC9872249 DOI: 10.1136/gutjnl-2021-325808] [Citation(s) in RCA: 78] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 05/25/2022] [Indexed: 02/01/2023]
Abstract
OBJECTIVE Programmed cell death protein 1 (PD-1) checkpoint inhibition and adoptive cellular therapy have had limited success in patients with microsatellite stable colorectal cancer liver metastases (CRLM). We sought to evaluate the effect of interleukin 10 (IL-10) blockade on endogenous T cell and chimeric antigen receptor T (CAR-T) cell antitumour function in CRLM slice cultures. DESIGN We created organotypic slice cultures from human CRLM (n=38 patients' tumours) and tested the antitumour effects of a neutralising antibody against IL-10 (αIL-10) both alone as treatment and in combination with exogenously administered carcinoembryonic antigen (CEA)-specific CAR-T cells. We evaluated slice cultures with single and multiplex immunohistochemistry, in situ hybridisation, single-cell RNA sequencing, reverse-phase protein arrays and time-lapse fluorescent microscopy. RESULTS αIL-10 generated a 1.8-fold increase in T cell-mediated carcinoma cell death in human CRLM slice cultures. αIL-10 significantly increased proportions of CD8+ T cells without exhaustion transcription changes, and increased human leukocyte antigen - DR isotype (HLA-DR) expression of macrophages. The antitumour effects of αIL-10 were reversed by major histocompatibility complex class I or II (MHC-I or MHC-II) blockade, confirming the essential role of antigen presenting cells. Interrupting IL-10 signalling also rescued murine CAR-T cell proliferation and cytotoxicity from myeloid cell-mediated immunosuppression. In human CRLM slices, αIL-10 increased CEA-specific CAR-T cell activation and CAR-T cell-mediated cytotoxicity, with nearly 70% carcinoma cell apoptosis across multiple human tumours. Pretreatment with an IL-10 receptor blocking antibody also potentiated CAR-T function. CONCLUSION Neutralising the effects of IL-10 in human CRLM has therapeutic potential as a stand-alone treatment and to augment the function of adoptively transferred CAR-T cells.
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Affiliation(s)
- Kevin M Sullivan
- Department of Surgery, University of Washington, Seattle, Washington, USA
| | - Xiuyun Jiang
- Department of Surgery, University of Washington, Seattle, Washington, USA
| | - Prajna Guha
- Immuno-Oncology Institute and Department of Medicine, Roger Williams Medical Center, Providence, Rhode Island, USA,Department of Surgery, Boston University School of Medicine, Boston, Massachusetts, USA
| | | | - Jason A Carter
- Department of Surgery, University of Washington, Seattle, Washington, USA
| | - Cynthia Hsu
- Department of Surgery, University of Washington, Seattle, Washington, USA
| | - Kevin P Labadie
- Department of Surgery, University of Washington, Seattle, Washington, USA
| | - Karan Kohli
- Department of Surgery, University of Washington, Seattle, Washington, USA,Brotman Baty Institute for Precision Medicine, Seattle, Washington, USA
| | - Heidi L Kenerson
- Department of Surgery, University of Washington, Seattle, Washington, USA
| | - Sara K Daniel
- Department of Surgery, University of Washington, Seattle, Washington, USA
| | - Xiaowei Yan
- Institute for Systems Biology, Seattle, Washington, USA
| | | | - Arezou Abbasi
- Department of Surgery, University of Washington, Seattle, Washington, USA
| | - Marina Chan
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Y David Seo
- Department of Surgery, University of Washington, Seattle, Washington, USA
| | - James O Park
- Department of Surgery, University of Washington, Seattle, Washington, USA
| | | | - Raymond S Yeung
- Department of Surgery, University of Washington, Seattle, Washington, USA
| | - Teresa S Kim
- Department of Surgery, University of Washington, Seattle, Washington, USA
| | - Taranjit S Gujral
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Qiang Tian
- Institute for Systems Biology, Seattle, Washington, USA .,National Research Center for Translational Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Steven C Katz
- Immuno-Oncology Institute and Department of Medicine, Roger Williams Medical Center, Providence, Rhode Island, USA,Department of Surgery, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Venu G Pillarisetty
- Department of Surgery, University of Washington, Seattle, Washington, USA .,Brotman Baty Institute for Precision Medicine, Seattle, Washington, USA
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11
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Lin L, Zeng X, Liang S, Wang Y, Dai X, Sun Y, Wu Z. Construction of a co-expression network and prediction of metastasis markers in colorectal cancer patients with liver metastasis. J Gastrointest Oncol 2022; 13:2426-2438. [PMID: 36388701 PMCID: PMC9660078 DOI: 10.21037/jgo-22-965] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 10/18/2022] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a common global malignancy associated with high invasiveness, high metastasis, and poor prognosis. CRC commonly metastasizes to the liver, where the treatment of metastasis is both difficult and an important topic in current CRC management. METHODS Microarrays data of human CRC with liver metastasis (CRCLM) were downloaded from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database to identify potential key genes. Differentially expressed (DE) genes (DEGs) and DEmiRNAs of primary CRC tumor tissues and metastatic liver tissues were identified. Microenvironment Cell Populations (MCP)-counter was used to estimate the abundance of immune cells in the tumor micro-environment (TME), and weighted gene correlation network analysis (WGCNA) was used to construct the co-expression network analysis. Gene Ontology and Kyoto Encyclopaedia of Gene and Genome (KEGG) pathway enrichment analyses were conducted, and the protein-protein interaction (PPI) network for the DEGs were constructed and gene modules were screened. RESULTS Thirty-five pairs of matched colorectal primary cancer and liver metastatic gene expression profiles were screened, and 610 DEGs (265 up-regulated and 345 down-regulated) and 284 DEmiRNAs were identified. The DEGs were mainly enriched in the complement and coagulation cascade pathways and renin secretion. Immune infiltrating cells including neutrophils, monocytic lineage, and cancer-associated fibroblasts (CAFs) differed significantly between primary tumor tissues and metastatic liver tissues. WGCN analysis obtained 12 modules and identified 62 genes with significant interactions which were mainly related to complement and coagulation cascade and the focal adhesion pathway. The best subset regression analysis and backward stepwise regression analysis were performed, and eight genes were determined, including F10, FGG, KNG1, MBL2, PROC, SERPINA1, CAV1, and SPP1. Further analysis showed four genes, including FGG, KNG1, CAV1, and SPP1 were significantly associated with CRCLM. CONCLUSIONS Our study implies complement and coagulation cascade and the focal adhesion pathway play a significant role in the development and progression of CRCLM, and FGG, KNG1, CAV1, and SPP1 may be metastatic markers for its early diagnosis.
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Affiliation(s)
- Lihong Lin
- Department of Anorectal Surgery, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Xiuxiu Zeng
- Department of Anorectal Surgery, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Shanyan Liang
- Department of Anorectal Surgery, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Yunzhi Wang
- School of Health Sciences, University of Sydney, Lidcombe, NSW, Australia
| | - Xiaoyu Dai
- Department of Anorectal Surgery, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Yuechao Sun
- Department of Anorectal Surgery, 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
| | - Zhou Wu
- Department of Anorectal Surgery, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China
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12
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Fang Y, Su C. Research Progress on the Microenvironment and Immunotherapy of Advanced Non-Small Cell Lung Cancer With Liver Metastases. Front Oncol 2022; 12:893716. [PMID: 35965533 PMCID: PMC9367973 DOI: 10.3389/fonc.2022.893716] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 06/22/2022] [Indexed: 12/03/2022] Open
Abstract
Lung cancer is a malignant tumor with the highest morbidity and mortality, and more than 75% of patients are diagnosed at an advanced stage. Liver metastases occur in 20% of non-small cell lung cancer patients, and their prognosis are poor. In recent years, immune checkpoint inhibitor monotherapy and combination therapy have made breakthrough progress in advanced Non-small cell lung cancer (NSCLC) patients. However, compared with the overall population, the liver metastases population was an independent prognostic factor for poor immunotherapy response. Whether and how immunotherapy can work in NSCLC patients with liver metastases is a major and unresolved challenge. Although more and more data have been disclosed, the research progress of NSCLC liver metastasis is still limited. How liver metastasis modulates systemic antitumor immunity and the drug resistance mechanisms of the liver immune microenvironment have not been elucidated. We systematically focused on non-small cell lung cancer patients with liver metastases, reviewed and summarized their pathophysiological mechanisms, immune microenvironment characteristics, and optimization of immunotherapy strategies.
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13
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Lin C, Yang H, Zhao W, Wang W. CTSB+ macrophage repress memory immune hub in the liver metastasis site of colorectal cancer patient revealed by multi-omics analysis. Biochem Biophys Res Commun 2022; 626:8-14. [DOI: 10.1016/j.bbrc.2022.06.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/06/2022] [Accepted: 06/10/2022] [Indexed: 12/24/2022]
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14
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Maisel BA, Yi M, Peck AR, Sun Y, Hooke JA, Kovatich AJ, Shriver CD, Hu H, Nevalainen MT, Tanaka T, Simone N, Wang LL, Rui H, Chervoneva I. Spatial Metrics of Interaction between CD163-Positive Macrophages and Cancer Cells and Progression-Free Survival in Chemo-Treated Breast Cancer. Cancers (Basel) 2022; 14:308. [PMID: 35053472 PMCID: PMC8773496 DOI: 10.3390/cancers14020308] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 01/04/2022] [Accepted: 01/05/2022] [Indexed: 02/07/2023] Open
Abstract
Tumor-associated macrophages (TAMs) promote progression of breast cancer and other solid malignancies via immunosuppressive, pro-angiogenic and pro-metastatic effects. Tumor-promoting TAMs tend to express M2-like macrophage markers, including CD163. Histopathological assessments suggest that the density of CD163-positive TAMs within the tumor microenvironment is associated with reduced efficacy of chemotherapy and unfavorable prognosis. However, previous analyses have required research-oriented pathologists to visually enumerate CD163+ TAMs, which is both laborious and subjective and hampers clinical implementation. Objective, operator-independent image analysis methods to quantify TAM-associated information are needed. In addition, since M2-like TAMs exert local effects on cancer cells through direct juxtacrine cell-to-cell interactions, paracrine signaling, and metabolic factors, we hypothesized that spatial metrics of adjacency of M2-like TAMs to breast cancer cells will have further information value. Immunofluorescence histo-cytometry of CD163+ TAMs was performed retrospectively on tumor microarrays of 443 cases of invasive breast cancer from patients who subsequently received adjuvant chemotherapy. An objective and automated algorithm was developed to phenotype CD163+ TAMs and calculate their density within the tumor stroma and derive several spatial metrics of interaction with cancer cells. Shorter progression-free survival was associated with a high density of CD163+ TAMs, shorter median cancer-to-CD163+ nearest neighbor distance, and a high number of either directly adjacent CD163+ TAMs (within juxtacrine proximity <12 μm to cancer cells) or communicating CD163+ TAMs (within paracrine communication distance <250 μm to cancer cells) after multivariable adjustment for clinical and pathological risk factors and correction for optimistic bias due to dichotomization.
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Affiliation(s)
- Brenton A. Maisel
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA; (B.A.M.); (M.Y.)
| | - Misung Yi
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA; (B.A.M.); (M.Y.)
| | - Amy R. Peck
- Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (A.R.P.); (Y.S.); (M.T.N.)
| | - Yunguang Sun
- Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (A.R.P.); (Y.S.); (M.T.N.)
| | - Jeffrey A. Hooke
- John P. Murtha Cancer Center, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, MD 20814, USA; (J.A.H.); (A.J.K.); (C.D.S.)
| | - Albert J. Kovatich
- John P. Murtha Cancer Center, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, MD 20814, USA; (J.A.H.); (A.J.K.); (C.D.S.)
| | - Craig D. Shriver
- John P. Murtha Cancer Center, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, MD 20814, USA; (J.A.H.); (A.J.K.); (C.D.S.)
| | - Hai Hu
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA 15963, USA;
| | - Marja T. Nevalainen
- Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (A.R.P.); (Y.S.); (M.T.N.)
| | - Takemi Tanaka
- Department of Pathology, University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Oklahoma City, OK 73104, USA;
| | - Nicole Simone
- Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA;
| | - Li Lily Wang
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA;
| | - Hallgeir Rui
- Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (A.R.P.); (Y.S.); (M.T.N.)
| | - Inna Chervoneva
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA; (B.A.M.); (M.Y.)
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15
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Pan S, Tang T, Wu Y, Zhang L, Song Z, Yu S. Identification and Validation of Immune-Related Prognostic Genes in the Tumor Microenvironment of Colon Adenocarcinoma. Front Genet 2022; 12:778153. [PMID: 35047006 PMCID: PMC8762242 DOI: 10.3389/fgene.2021.778153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 12/07/2021] [Indexed: 11/13/2022] Open
Abstract
The tumor microenvironment (TME) has been shown to be involved in angiogenesis, tumor metastasis, and immune response, thereby affecting the treatment and prognosis of patients. This study aims to identify genes that are dysregulated in the TME of patients with colon adenocarcinoma (COAD) and to evaluate their prognostic value based on RNA omics data. We obtained 512 COAD samples from the Cancer Genome Atlas (TCGA) database and 579 COAD patients from the independent dataset (GSE39582) in the Gene Expression Omnibus (GEO) database. The immune/stromal/ESTIMATE score of each patient based on their gene expression was calculated using the ESTIMATE algorithm. Kaplan-Meier survival analysis, Cox regression analysis, gene functional enrichment analysis, and protein-protein interaction (PPI) network analysis were performed. We found that immune and stromal scores were significantly correlated with COAD patients' overall survival (log rank p < 0.05). By comparing the high immune/stromal score group with the low score group, we identified 688 intersection differentially expressed genes (DEGs) from the TCGA dataset (663 upregulated and 25 downregulated). The functional enrichment analysis of intersection DEGs showed that they were mainly enriched in the immune process, cell migration, cell motility, Toll-like receptor signaling pathway, and PI3K-Akt signaling pathway. The hub genes were revealed by PPI network analysis. Through Kaplan-Meier and Cox analysis, four TME-related genes that were significantly related to the prognosis of COAD patients were verified in GSE39582. In addition, we uncovered the relationship between the four prognostic genes and immune cells in COAD. In conclusion, based on the RNA expression profiles of 1091 COAD patients, we screened four genes that can predict prognosis from the TME, which may serve as candidate prognostic biomarkers for COAD.
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Affiliation(s)
| | | | | | | | | | - Sisi Yu
- Department of Pathology, Ruian People’s Hospital, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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16
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Kou Y, Li Z, Sun Q, Yang S, Wang Y, Hu C, Gu H, Wang H, Xu H, Li Y, Kou Y, Han B. Prognostic value and predictive biomarkers of phenotypes of tumor-associated macrophages in colorectal cancer. Scand J Immunol 2021; 95:e13137. [PMID: 34964155 PMCID: PMC9286461 DOI: 10.1111/sji.13137] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 10/29/2021] [Accepted: 12/26/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND The roles of different subtypes of tumor-associated macrophages (TAMs) in predicting the prognosis of colorectal cancer (CRC) remain controversial. In this study, different subtypes of TAMs were investigated as prognostic and predictive biomarkers for CRC. METHODS Expressions of CD68, CD86 and CD163 were investigated by immunohistochemistry (IHC) and immunofluorescence (IF), and the correlation between the expression of CD86 and CD163 was calculated in colorectal cancer tissues from 64 CRC patients. RESULTS The results showed that high expressions of CD86+ and CD68+ CD86+ TAMs as well as low expression of CD163+ and CD68+ CD163+ TAMs were significantly associated with favorable overall survival (OS). The level of CD86 protein expression showed a negative correlation with CD163 protein expression. In addition, CD86 protein expression remarkably negative correlated with tumor differentiation and tumor node metastasis (TNM) stage, while CD163 protein expression significantly positive correlated with tumor differentiation and tumor size. As an independent risk factor, high expression of CD86 TAMs had prominently favorable prognostic efficacy while high expression of CD68+ CD163+ TAMs had significantly poor prognostic efficacy. CONCLUSIONS These results indicate that CD86+ and CD68+ CD163+ TAMs as prognostic and predictive biomarkers for CRC.
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Affiliation(s)
- Yu Kou
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, 225000, Jiangsu, China.,Department of Traditional Chinese Medicine Affiliated Hospital, Yangzhou University, 225000, Jiangsu, China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, 225000, Jiangsu, China
| | - Zhuoqun Li
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, 225000, Jiangsu, China.,Department of Traditional Chinese Medicine Affiliated Hospital, Yangzhou University, 225000, Jiangsu, China
| | - Qidi Sun
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, 225000, Jiangsu, China.,Department of Traditional Chinese Medicine Affiliated Hospital, Yangzhou University, 225000, Jiangsu, China
| | - Shengnan Yang
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, 225000, Jiangsu, China.,Department of Traditional Chinese Medicine Affiliated Hospital, Yangzhou University, 225000, Jiangsu, China
| | - Yunshuai Wang
- Department of General Surgery, Luoyang Central Hospital Affiliated of Zhengzhou University, 471000, Henan, China
| | - Chen Hu
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, 225000, Jiangsu, China.,Department of Traditional Chinese Medicine Affiliated Hospital, Yangzhou University, 225000, Jiangsu, China
| | - Huijie Gu
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, 225000, Jiangsu, China.,Department of Traditional Chinese Medicine Affiliated Hospital, Yangzhou University, 225000, Jiangsu, China
| | - Huangjian Wang
- Department of General Surgery, Luoyang Central Hospital Affiliated of Zhengzhou University, 471000, Henan, China
| | - Hairong Xu
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, 225000, Jiangsu, China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, 225000, Jiangsu, China
| | - Yan Li
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, 225000, Jiangsu, China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, 225000, Jiangsu, China
| | - Yu Kou
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, 225000, Jiangsu, China.,Department of Traditional Chinese Medicine Affiliated Hospital, Yangzhou University, 225000, Jiangsu, China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, 225000, Jiangsu, China
| | - Baowei Han
- Department of General Surgery, Luoyang Central Hospital Affiliated of Zhengzhou University, 471000, Henan, China
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17
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Chen Y, Zheng X, Wu C. The Role of the Tumor Microenvironment and Treatment Strategies in Colorectal Cancer. Front Immunol 2021; 12:792691. [PMID: 34925375 PMCID: PMC8674693 DOI: 10.3389/fimmu.2021.792691] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/15/2021] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer (CRC) has the second highest mortality rate among all cancers worldwide. Surgery, chemotherapy, radiotherapy, molecular targeting and other treatment methods have significantly prolonged the survival of patients with CRC. Recently, the emergence of tumor immunotherapy represented by immune checkpoint inhibitors (ICIs) has brought new immunotherapy options for the treatment of advanced CRC. As the efficacy of ICIs is closely related to the tumor immune microenvironment (TME), it is necessary to clarify the relationship between the immune microenvironment of CRC and the efficacy of immunotherapy to ensure that the appropriate drugs are selected. We herein review the latest research progress in the immune microenvironment and strategies related to immunotherapy for CRC. We hope that this review helps in the selection of appropriate treatment strategies for CRC patients.
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Affiliation(s)
- Yaping Chen
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Xiao Zheng
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Changping Wu
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
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18
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The Colorectal Cancer Tumor Microenvironment and Its Impact on Liver and Lung Metastasis. Cancers (Basel) 2021; 13:cancers13246206. [PMID: 34944826 PMCID: PMC8699466 DOI: 10.3390/cancers13246206] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/02/2021] [Accepted: 12/02/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Colorectal cancer (CRC) is the third most common cancer worldwide. Metastasis to secondary organs, such as the liver and lungs, is a key driver of CRC-related mortality. The tumor microenvironment, which consists of the primary cancer cells, as well as associated support and immune cells, significantly affects the behavior of CRC cells at the primary tumor site, as well as in metastatic lesions. In this paper, we review the role of the individual components of the tumor microenvironment on tumor progression, immune evasion, and metastasis, and we discuss the implications of these components on antitumor therapies. Abstract Colorectal cancer (CRC) is the third most common malignancy and the second most common cause of cancer-related mortality worldwide. A total of 20% of CRC patients present with distant metastases, most frequently to the liver and lung. In the primary tumor, as well as at each metastatic site, the cellular components of the tumor microenvironment (TME) contribute to tumor engraftment and metastasis. These include immune cells (macrophages, neutrophils, T lymphocytes, and dendritic cells) and stromal cells (cancer-associated fibroblasts and endothelial cells). In this review, we highlight how the TME influences tumor progression and invasion at the primary site and its function in fostering metastatic niches in the liver and lungs. We also discuss emerging clinical strategies to target the CRC TME.
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19
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Chen J, Ding J, Huang W, Sun L, Chen J, Liu Y, Zhan Q, Gao G, He X, Qiu G, Long P, Wei L, Lu Z, Sun Y. DNASE1L3 as a Novel Diagnostic and Prognostic Biomarker for Lung Adenocarcinoma Based on Data Mining. Front Genet 2021; 12:699242. [PMID: 34868195 PMCID: PMC8636112 DOI: 10.3389/fgene.2021.699242] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 10/18/2021] [Indexed: 11/13/2022] Open
Abstract
Previous researches have highlighted that low-expressing deoxyribonuclease1-like 3 (DNASE1L3) may play a role as a potential prognostic biomarker in several cancers. However, the diagnosis and prognosis roles of DNASE1L3 gene in lung adenocarcinoma (LUAD) remain largely unknown. This research aimed to explore the diagnosis value, prognostic value, and potential oncogenic roles of DNASE1L3 in LUAD. We performed bioinformatics analysis on LUAD datasets downloaded from TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus), and jointly analyzed with various online databases. We found that both the mRNA and protein levels of DNASE1L3 in patients with LUAD were noticeably lower than that in normal tissues. Low DNASE1L3 expression was significantly associated with higher pathological stages, T stages, and poor prognosis in LUAD cohorts. Multivariate analysis revealed that DNASE1L3 was an independent factor affecting overall survival (HR = 0.680, p = 0.027). Moreover, decreased DNASE1L3 showed strong diagnostic efficiency for LUAD. Results indicated that the mRNA level of DNASE1L3 was positively correlated with the infiltration of various immune cells, immune checkpoints in LUAD, especially with some m6A methylation regulators. In addition, enrichment function analysis revealed that the co-expressed genes may participate in the process of intercellular signal transduction and transmission. GSEA indicated that DNASE1L3 was positively related to G protein-coupled receptor ligand biding (NES = 1.738; P adjust = 0.044; FDR = 0.033) and G alpha (i) signaling events (NES = 1.635; P adjust = 0.044; FDR = 0.033). Our results demonstrated that decreased DNASE1L3 may serve as a novel diagnostic and prognostic biomarker associating with immune infiltrates in lung adenocarcinoma.
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Affiliation(s)
- Jianlin Chen
- Departments of Clinical Laboratory of Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, China
| | - Junping Ding
- Departments of General surgery of Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, China
| | - Wenjie Huang
- Departments of Clinical Laboratory of Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, China
| | - Lin Sun
- Departments of Clinical Laboratory of Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, China
| | - Jinping Chen
- Departments of Respiratory Medicine of Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, China
| | - Yangyang Liu
- Departments of Clinical Laboratory of Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, China
| | - Qianmei Zhan
- Departments of Clinical Laboratory of Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, China
| | - Gan Gao
- Departments of Clinical Laboratory of Liuzhou Maternity and Child Healthcare Hospital, Liuzhou, China
| | - Xiaoling He
- Department of Clinical Laboratory of People's Hospital Rong an County, Liuzhou, China
| | - Guowen Qiu
- Departments of Orthopedics of Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, China
| | - Peiying Long
- Department of Clinical Laboratory of People's Hospital Rong an County, Liuzhou, China
| | - Lishu Wei
- Departments of Clinical Laboratory of Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, China
| | - Zhenni Lu
- Departments of Clinical Laboratory of Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, China
| | - Yifan Sun
- Departments of Clinical Laboratory of Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, China
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20
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Stage I-IV Colorectal Cancer Prognosis Can Be Predicted by Type and Number of Intratumoral Macrophages and CLEVER-1 + Vessel Density. Cancers (Basel) 2021; 13:cancers13235988. [PMID: 34885098 PMCID: PMC8656733 DOI: 10.3390/cancers13235988] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/20/2021] [Accepted: 11/24/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Tumor-associated macrophages can either promote or prevent cancer growth depending on factors such as macrophage polarization status, tumor type, and disease stage. Macrophages and vessels interact with each other, and the number of lymphatic vessels also affects cancer survival. CLEVER-1 is a protein expressed both on immunosuppressive M2 macrophages and lymphatic vessels. The aim of this study was to validate our previous results regarding the prognostic role of CLEVER-1+ macrophages, CD68+ macrophages, and CLEVER-1+ lymphatic vessels in stage I–IV colorectal cancer. The results indicate that the prognostic role of tumor-associated macrophages and lymphatic vessels changes during disease progression. The findings resemble our earlier results, but are not completely equal, which may be due to the different types of tumor samples used in the two studies (whole section vs. tissue microarray). Abstract Macrophages, which are key players in the tumor microenvironment and affect the prognosis of many cancers, interact with lymphatic vessels in tumor tissue. However, the prognostic role of tumor-associated macrophages (TAM) and lymphatic vessels in human colorectal cancer (CRC) remains controversial. We investigated the prognostic role of CD68+ and CLEVER-1+ (common lymphatic endothelial and vascular endothelial receptor 1) TAMs in addition to CLEVER-1+ lymphatic vessels in 498 stage I–IV CRC patients. The molecular markers were detected by immunohistochemical (IHC) analysis. The results showed that, in early stage I CRC and in young patients (age below median, ≤67.4 years), a high number of CD68+ and CLEVER-1+ TAMs was associated with longer disease-specific survival (DSS). In early stage I CRC, high intratumoral CLEVER-1+ lymphatic vessel density (LVD) predicted a favorable prognosis, whereas the opposite pattern was observed in stage II CRC. The highest density of CLEVER-1+ lymphatic vessels was found in metastatic disease. The combination of intratumoral CLEVER-1+ lymphatic vesselhigh + CD68+ TAMlow was associated with poor DSS in stage I–IV rectal cancer. The present results indicate that the prognostic significance of intratumoral macrophages and CLEVER-1+ lymphatic vessels differs according to disease stage, reflecting the dynamic changes occurring in the tumor microenvironment during disease progression.
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21
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Wei Z, Yang M, Feng M, Wu Z, Rosin-Arbesfeld R, Dong J, Zhu D. Inhibition of BCL9 Modulates the Cellular Landscape of Tumor-Associated Macrophages in the Tumor Immune Microenvironment of Colorectal Cancer. Front Pharmacol 2021; 12:713331. [PMID: 34566638 PMCID: PMC8461101 DOI: 10.3389/fphar.2021.713331] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 08/20/2021] [Indexed: 01/01/2023] Open
Abstract
Tumor-associated macrophages (TAMs) are an indispensable part of the tumor microenvironment (TME), and they likely play a negative rather than positive role in cancer treatment. However, the cellular landscape and transcriptional profile regulation of TAMs in the case of tumor gene inactivation or chemical interference remains unclear. The B-cell lymphoma 9/B-cell lymphoma 9-like (BCL9/BCL9L) is a critical transcription co-factor of β-catenin. Suppression of Bcl9 inhibits tumor growth in mouse models of colorectal cancer (CRC). Here, we studied the TAMs of CRC by single-cell sequencing. Bcl9 depletion caused macrophage polarization inhibition from M0 to M2 and changed the CRC TME, which further interferes with the inflammation of M0 and M1. The transcription factor regulating these processes may be related to the Wnt signaling pathway from multiple levels. Furthermore, we also found that the cells delineated from monocyte to NK-like non-functioning cells were significantly different in the BCL9-deprived population. Combining these data, we proposed a TAM-to-NK score to evaluate the dynamic balance in TME of monocyte/TAM cells and NK-like non-functioning cells in The Cancer Genome Atlas (TCGA) clinical samples to verify the clinical significance. We demonstrated that the cell type balance and transcription differences of TAMs regulated by BCL9-driven Wnt signaling affected immune surveillance and inflammation of cancer, ultimately affecting patients' prognosis. We thereby highlighted the potential of targeting Wnt signaling pathway through cancer immunotherapy.
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Affiliation(s)
- Zhuang Wei
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Key Laboratory of Systems Biology, Innovation Center for Cell Signaling Network, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Mengxuan Yang
- Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Mei Feng
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Zhongen Wu
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Rina Rosin-Arbesfeld
- Department of Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Jibin Dong
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Di Zhu
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Key Laboratory of Smart Drug Delivery, State Key Laboratory of Molecular Engineering of Polymers, School of Pharmacy, Ministry of Education, Fudan University, Shanghai, China.,Shanghai Engineering Research Center of ImmunoTherapeutics, Fudan University, Shanghai, China
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22
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Kunk PR, Dougherty SC, Lynch K, Whitehair R, Meneveau M, Obeid JM, Winters K, Ju JY, Stelow EB, Bauer TW, Slingluff CL, Rahma OE. Myeloid Cell Infiltration Correlates With Prognosis in Cholangiocarcinoma and Varies Based on Tumor Location. J Immunother 2021; 44:254-263. [PMID: 34191790 PMCID: PMC8373662 DOI: 10.1097/cji.0000000000000378] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 05/03/2021] [Indexed: 01/04/2023]
Abstract
Cholangiocarcinoma (CC) is an uncommon malignancy with increasing incidence and dismal prognosis. We conducted a comprehensive analysis of the CC tumor immune microenvironment (TIME) based on tumor location to identify therapeutic targets. We hypothesized that the TIME of CC would vary by primary tumor location and that high tumor infiltration by CD8+ T cells and low infiltration by M2 macrophages would be associated with improved survival. A retrospective analysis was conducted of 99 CC tumor samples surgically resected between 2000 and 2014. Tissue microarrays were constructed from each tumor and stained by immunohistochemistry for 24 markers of immune cells, immune activation or inhibition, programmed cell death-ligand 1, and mesothelin. Most tumors were amply infiltrated with by CD4+, CD8+, and FoxP3+ T cells, as well as by myeloid cells. Mesothelin expression ≥1+ by immunohistochemistry was found in 68% of tumors. We identified higher densities of M1 macrophages in primary distal extrahepatic CC, as well as metastatic lesions. Mesothelin expression was also significantly higher in distal extrahepatic CC. There was no association with survival of infiltration by CD4+, CD8+, or FoxP3+ T cells, mesothelin expression, or programmed cell death-ligand 1 percentage expression, however, high CD14+ myeloid cells and high CD163+ M2 macrophages were associated with worse survival. In conclusion, the CC TIME is a heterogenous milieu highly infiltrated by innate and adaptive immune cells, which differs based on primary tumor location and between primary tumors and metastatic lesions. The correlation of intratumoral M2 macrophages and myeloid cells with a worse prognosis may suggest promising immunotherapeutic targets in CC.
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Affiliation(s)
- Paul R. Kunk
- Department of Medicine, Division of Hematology-Oncology, University of Virginia Health System, Charlottesville, VA, United States
| | - Sean C. Dougherty
- Department of Medicine, Division of Hematology-Oncology, University of Virginia Health System, Charlottesville, VA, United States
| | - Kevin Lynch
- Department of Surgery, University of Virginia Health System, Charlottesville, VA, United States
| | - Rachel Whitehair
- Department of Pathology, Division of Anatomic Pathology, University of Virginia Health System, Charlottesville, VA, United States
| | - Max Meneveau
- Department of Surgery, University of Virginia Health System, Charlottesville, VA, United States
| | - Joseph M. Obeid
- Department of Surgery, Stony Brook University Hospital, Stony Brook, NY, United States
| | - Kevin Winters
- Department of Medicine, Division of Hematology-Oncology, University of Virginia Health System, Charlottesville, VA, United States
| | - Jennifer Y. Ju
- Department of Pathology, Division of Anatomic Pathology, University of Virginia Health System, Charlottesville, VA, United States
| | - Edward B. Stelow
- Department of Pathology, Division of Anatomic Pathology, University of Virginia Health System, Charlottesville, VA, United States
| | - Todd W. Bauer
- Department of Surgery, University of Virginia Health System, Charlottesville, VA, United States
| | - Craig L. Slingluff
- Department of Surgery, University of Virginia Health System, Charlottesville, VA, United States
| | - Osama E. Rahma
- Departement of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
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23
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Wang H, Tian T, Zhang J. Tumor-Associated Macrophages (TAMs) in Colorectal Cancer (CRC): From Mechanism to Therapy and Prognosis. Int J Mol Sci 2021; 22:ijms22168470. [PMID: 34445193 PMCID: PMC8395168 DOI: 10.3390/ijms22168470] [Citation(s) in RCA: 218] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 07/30/2021] [Accepted: 08/02/2021] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is a malignant tumor in the digestive system whose incidence and mortality is high-ranking among tumors worldwide. The initiation and progression of CRC is a complex process involving genetic alterations in cancer cells and multiple factors from the surrounding tumor cell microenvironment. As accumulating evidence has shown, tumor-associated macrophages (TAMs)—as abundant and active infiltrated inflammatory cells in the tumor microenvironment (TME)—play a crucial role in CRC. This review focuses on the different mechanisms of TAM in CRC, including switching of phenotypical subtypes; promoting tumor proliferation, invasion, and migration; facilitating angiogenesis; mediating immunosuppression; regulating metabolism; and interacting with the microbiota. Although controversy remains in clinical evidence regarding the role of TAMs in CRC, clarifying their significance in therapy and the prognosis of CRC may shed new light on the optimization of TAM-centered approaches in clinical care.
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Affiliation(s)
- Hui Wang
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning 530021, China;
| | - Tian Tian
- College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China
- Correspondence: (T.T.); (J.Z.)
| | - Jinhua Zhang
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning 530021, China;
- College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China
- Correspondence: (T.T.); (J.Z.)
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24
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Tumor Microenvironment in Metastatic Colorectal Cancer: The Arbitrator in Patients' Outcome. Cancers (Basel) 2021; 13:cancers13051130. [PMID: 33800796 PMCID: PMC7961499 DOI: 10.3390/cancers13051130] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 02/25/2021] [Accepted: 03/02/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Colorectal cancer accounts for approximately 10% of all annually diagnosed cancers worldwide being liver metastasis, the most common cause of death in patients with colorectal cancer. The interplay between tumor and stromal cells in the primary tumor microenvironment and at distant metastases are rising in importance as potential mechanisms of the tumor progression. In this review we discuss the new biomarkers derived from tumor microenvironment and liquid biopsy as emerging prognostic and treatments response markers for metastatic colorectal cancer. We also review the developing new clinical strategies based on tumor microenvironmental cells to tackle metastatic disease in metastatic colorectal cancer patients. Abstract Colorectal cancer (CRC) is one of the most common cancers in western countries. Its mortality rate varies greatly, depending on the stage of the disease. The main cause of CRC mortality is metastasis, which most commonly affects the liver. The role of tumor microenvironment in tumor initiation, progression and metastasis development has been widely studied. In this review we summarize the role of the tumor microenvironment in the liver pre-metastatic niche formation, paying attention to the distant cellular crosstalk mediated by exosomes. Moreover, and based on the prognostic and predictive capacity of alterations in the stromal compartment of tumors, we describe the role of tumor microenvironment cells and related liquid biopsy biomarkers in the delivery of precise medication for metastatic CRC. Finally, we evaluate the different clinical strategies to prevent and treat liver metastatic disease, based on the targeting of the tumor microenvironment. Specifically, targeting angiogenesis pathways and regulating immune response are two important research pipelines that are being widely developed and promise great benefits.
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25
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Grewal S, Oosterling SJ, van Egmond M. Surgery for Colorectal Cancer: A Trigger for Liver Metastases Development? New Insights into the Underlying Mechanisms. Biomedicines 2021; 9:biomedicines9020177. [PMID: 33670204 PMCID: PMC7916916 DOI: 10.3390/biomedicines9020177] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/05/2021] [Accepted: 02/07/2021] [Indexed: 12/24/2022] Open
Abstract
Surgery is a crucial intervention and provides the best chance of cure for patients with colorectal cancer. Experimental and clinical evidence, however, suggests that paradoxically surgery itself may precipitate or accelerate tumor recurrence and/or liver metastasis development. This review addresses the various aspects of surgery-induced metastasis formation and sheds light on the role of inflammation as potential trigger for metastasis development. Understanding these mechanisms may provide potential new perioperative interventions to improve treatment outcomes, and as such could transform the perioperative timeframe from a facilitator of metastatic progression to a window of opportunity to reduce the risk of liver metastasis development. Ultimately, this can potentially improve long-term survival rates and quality of life in patients with colorectal cancer.
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Affiliation(s)
- Simran Grewal
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Centers, 1007 MB Amsterdam, The Netherlands;
- Department of Surgery, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands
- Correspondence: ; Tel.: +31-20-4448080
| | | | - Marjolein van Egmond
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Centers, 1007 MB Amsterdam, The Netherlands;
- Department of Surgery, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands
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26
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Yoon PS, Del Piccolo N, Shirure VS, Peng Y, Kirane A, Canter RJ, Fields RC, George SC, Gholami S. Advances in Modeling the Immune Microenvironment of Colorectal Cancer. Front Immunol 2021; 11:614300. [PMID: 33643296 PMCID: PMC7902698 DOI: 10.3389/fimmu.2020.614300] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 12/29/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related death in the US. CRC frequently metastasizes to the liver and these patients have a particularly poor prognosis. The infiltration of immune cells into CRC tumors and liver metastases accurately predicts disease progression and patient survival. Despite the evident influence of immune cells in the CRC tumor microenvironment (TME), efforts to identify immunotherapies for CRC patients have been limited. Here, we argue that preclinical model systems that recapitulate key features of the tumor microenvironment-including tumor, stromal, and immune cells; the extracellular matrix; and the vasculature-are crucial for studies of immunity in the CRC TME and the utility of immunotherapies for CRC patients. We briefly review the discoveries, advantages, and disadvantages of current in vitro and in vivo model systems, including 2D cell culture models, 3D culture systems, murine models, and organ-on-a-chip technologies.
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Affiliation(s)
- Paul Sukwoo Yoon
- Department of Surgery, University of California, Davis, Sacramento, CA, United States
| | - Nuala Del Piccolo
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, United States
| | - Venktesh S Shirure
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, United States
| | - Yushuan Peng
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, United States
| | - Amanda Kirane
- Department of Surgery, University of California, Davis, Sacramento, CA, United States
| | - Robert J Canter
- Department of Surgery, University of California, Davis, Sacramento, CA, United States
| | - Ryan C Fields
- Department of Surgery, The Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States
| | - Steven C George
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, United States
| | - Sepideh Gholami
- Department of Surgery, University of California, Davis, Sacramento, CA, United States
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27
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Reidy E, Leonard NA, Treacy O, Ryan AE. A 3D View of Colorectal Cancer Models in Predicting Therapeutic Responses and Resistance. Cancers (Basel) 2021; 13:E227. [PMID: 33435170 PMCID: PMC7827038 DOI: 10.3390/cancers13020227] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/05/2021] [Accepted: 01/07/2021] [Indexed: 12/12/2022] Open
Abstract
Although there have been many advances in recent years for the treatment of colorectal cancer (CRC), it still remains the third most common cause of cancer-related deaths worldwide. Many patients with late stage CRC display resistance to multiple different therapeutics. An important aspect in developing effective therapeutics for CRC patients is understanding the interactions that take place in the tumor microenvironment (TME), as it has been shown to contribute to drug resistance in vivo. Much research over the past 100 years has focused on 2D monolayer cultures or in vivo studies, however, the efficacy in translating these to the clinic is very low. More recent studies are turning towards developing an effective 3D model of CRC that is clinically relevant, that can recapitulate the TME in vitro and bridge the gap between 2D cultures and in vivo studies, with the aim of reducing the use of animal models in the future. This review summarises the advantages and limitations of different 3D CRC models. It emphasizes how different 3D models may be optimised to study cellular and extracellular interactions that take place in the TME of CRC in an effort to allow the development of more translatable effective treatment options for patients.
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Affiliation(s)
- Eileen Reidy
- Lambe Institute for Translational research, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, H91 V4AY Galway, Ireland; (E.R.); (N.A.L.); (O.T.)
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, H91 W2TY Galway, Ireland
- Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, H91 W5P7 Galway, Ireland
- CÚRAM, SFI Research Centre for Medical Devices, NUI Galway, H91 W2TY Galway, Ireland
| | - Niamh A. Leonard
- Lambe Institute for Translational research, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, H91 V4AY Galway, Ireland; (E.R.); (N.A.L.); (O.T.)
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, H91 W2TY Galway, Ireland
- Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, H91 W5P7 Galway, Ireland
| | - Oliver Treacy
- Lambe Institute for Translational research, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, H91 V4AY Galway, Ireland; (E.R.); (N.A.L.); (O.T.)
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, H91 W2TY Galway, Ireland
- Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, H91 W5P7 Galway, Ireland
| | - Aideen E. Ryan
- Lambe Institute for Translational research, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, H91 V4AY Galway, Ireland; (E.R.); (N.A.L.); (O.T.)
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, H91 W2TY Galway, Ireland
- Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, H91 W5P7 Galway, Ireland
- CÚRAM, SFI Research Centre for Medical Devices, NUI Galway, H91 W2TY Galway, Ireland
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28
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Kroemer M, Turco C, Spehner L, Viot J, Idirène I, Bouard A, Renaude E, Deschamps M, Godet Y, Adotévi O, Limat S, Heyd B, Jary M, Loyon R, Borg C. Investigation of the prognostic value of CD4 T cell subsets expanded from tumor-infiltrating lymphocytes of colorectal cancer liver metastases. J Immunother Cancer 2020; 8:jitc-2020-001478. [PMID: 33229508 PMCID: PMC7684804 DOI: 10.1136/jitc-2020-001478] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/16/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The positive role of CD8+ tumor-infiltrating lymphocytes (TIL) in patients with colorectal cancer (CRC) has been well described but the prognostic value of CD4 T cell subsets remained to be investigated. In this study, we expanded TIL from surgically resected liver metastases of patients with CRC and characterized the phenotype and the prognostic value of expanded-CD4 T cells. METHODS Liver metastases were surgically resected from 23 patients with CRC. Tumors were enzymatically digested and cultured in high dose of interleukin-2 for up to 5 weeks. T cell phenotype and reactivity of cultured-T cells were measured by flow cytometry and correlated with patients' clinical outcomes. RESULTS We successfully expanded 21 over 23 TIL from liver metastases of patients with CRC. Interestingly, we distinguished two subsets of expanded T cells based on T cell immunoglobulin mucin domain-containing protein 3 (TIM-3) expression. Medians fold expansion of expanded T cells after rapid expansion protocol was higher in CD3+TIM-3low cultures. In an attempt to investigate the correlation between the phenotype of expanded CD4 T cells and clinical outcomes, we observed on one hand that the level of Tregs in culture as well as the expression of both PD1 and TIM-3 by expanded T cells was not correlated to the clinical outcomes. Interestingly, on the other hand, cultures containing high levels of Th17 cells were associated with a poor prognosis (p=0.0007). CONCLUSIONS Our data confirmed the presence of Th17 cells in expanded T cells from liver metastases. Among CD4 T cell characteristics investigated, TIM-3 but not programmed cell death protein 1 predicted the expansion capacity of TIL while only the Th17 phenotype showed correlation with patients' survival, suggesting a particular role of this T cell subset in CRC immune contexture. TRIAL REGISTRATION NUMBER NCT02817178.
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Affiliation(s)
- Marie Kroemer
- INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, University of Bourgogne Franche-Comté, F-25000 Besançon, France .,Department of Pharmacy, University hospital of Besançon, F-25000 Besançon, France
| | - Celia Turco
- INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, University of Bourgogne Franche-Comté, F-25000 Besançon, France.,Department of Digestive and Oncologic Surgery, Liver Transplantation Unit, University hospital of Besançon, F-25000 Besançon, France
| | - Laurie Spehner
- INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, University of Bourgogne Franche-Comté, F-25000 Besançon, France
| | - Julien Viot
- INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, University of Bourgogne Franche-Comté, F-25000 Besançon, France.,Department of Medical Oncology, University hospital of Besançon, F-25000 Besançon, France
| | - Idir Idirène
- INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, University of Bourgogne Franche-Comté, F-25000 Besançon, France
| | - Adeline Bouard
- INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, University of Bourgogne Franche-Comté, F-25000 Besançon, France.,ITAC platform, University of Bourgogne Franche-Comté, F-25000 Besançon, France
| | - Elodie Renaude
- INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, University of Bourgogne Franche-Comté, F-25000 Besançon, France
| | - Marina Deschamps
- INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, University of Bourgogne Franche-Comté, F-25000 Besançon, France
| | - Yann Godet
- INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, University of Bourgogne Franche-Comté, F-25000 Besançon, France
| | - Olivier Adotévi
- INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, University of Bourgogne Franche-Comté, F-25000 Besançon, France.,Department of Medical Oncology, University hospital of Besançon, F-25000 Besançon, France
| | - Samuel Limat
- INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, University of Bourgogne Franche-Comté, F-25000 Besançon, France.,Department of Pharmacy, University hospital of Besançon, F-25000 Besançon, France
| | - Bruno Heyd
- INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, University of Bourgogne Franche-Comté, F-25000 Besançon, France.,Department of Digestive and Oncologic Surgery, Liver Transplantation Unit, University hospital of Besançon, F-25000 Besançon, France
| | - Marine Jary
- INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, University of Bourgogne Franche-Comté, F-25000 Besançon, France.,Department of Medical Oncology, University hospital of Besançon, F-25000 Besançon, France
| | - Romain Loyon
- INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, University of Bourgogne Franche-Comté, F-25000 Besançon, France
| | - Christophe Borg
- INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, University of Bourgogne Franche-Comté, F-25000 Besançon, France.,Department of Medical Oncology, University hospital of Besançon, F-25000 Besançon, France.,ITAC platform, University of Bourgogne Franche-Comté, F-25000 Besançon, France
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29
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Huang WJ, Wang X, Zhang ML, Li L, Wang RT. Association between apoptosis inhibitor of macrophage and microsatellite instability status in colorectal cancer. BMC Gastroenterol 2020; 20:373. [PMID: 33172404 PMCID: PMC7654032 DOI: 10.1186/s12876-020-01520-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 11/02/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The microsatellite instability (MSI) in colorectal cancer (CRC) has a more favorable clinical outcome and is characterized by highly upregulated expression of various immunological checkpoints than microsatellite stable (MSS) tumors. Apoptosis inhibitor of macrophage (AIM) is a circulating protein and circulates throughout the body to remove cellular debris. The aim of this study was to evaluate the association between MSI status and AIM levels in CRC patients. METHODS In this study, we evaluated the levels of AIM by Enzyme Linked Immuno-Sorbent Assay (ELISA) in serum of 430 CRC patients. All patients' clinical and laboratory characteristics at initial diagnosis were collected. The relationship between AIM levels and MSI status was examined. RESULTS 64 patients (14.9%) were identified as having MSI-H (high-frequency MSI) and 366 casess (85.1%) having MSS. Patients with an MSI-H phenotype had lower AIM levels compared with MSS patients. Moreover, AIM levels were correlated with histological type and MSI status. Logistic regression analysis revealed that decreased AIM levels were independently associated with MSI-H phenotype after adjusting confounding factors. CONCLUSION Reduced AIM levels are associated with MSI-H subtyping of CRC. Further research on the involvement of AIM in MSI-H CRC is needed.
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Affiliation(s)
- Wen-Juan Huang
- Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin Medical University, No. 150 Haping ST, Nangang District, Harbin, Heilongjiang, 150081, China
| | - Xin Wang
- Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin Medical University, No. 150 Haping ST, Nangang District, Harbin, Heilongjiang, 150081, China
| | - Meng-Lin Zhang
- Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin Medical University, No. 150 Haping ST, Nangang District, Harbin, Heilongjiang, 150081, China
| | - Li Li
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, No. 150 Haping ST, Nangang District, HarbinHeilongjiang, 150081, China.
| | - Rui-Tao Wang
- Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin Medical University, No. 150 Haping ST, Nangang District, Harbin, Heilongjiang, 150081, China.
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30
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Jeremiasen M, Borg D, Hedner C, Svensson M, Nodin B, Leandersson K, Johansson J, Jirström K. Tumor-Associated CD68 +, CD163 +, and MARCO + Macrophages as Prognostic Biomarkers in Patients With Treatment-Naïve Gastroesophageal Adenocarcinoma. Front Oncol 2020; 10:534761. [PMID: 33194593 PMCID: PMC7645217 DOI: 10.3389/fonc.2020.534761] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 08/28/2020] [Indexed: 12/19/2022] Open
Abstract
Background: Despite improvements in surgical methodologies and perioperative chemo- and radiotherapy, the prognosis for patients with esophageal and gastric cancer remains poor. Hence, there is a great need to identify complementary biomarkers for improved treatment stratification. Tumor-infiltrating immune cells have been shown to impact on outcome in many types of cancer, including gastroesophageal cancer. The aim of this present study was to examine the prognostic value of tumor-infiltrating macrophages in gastroesophageal adenocarcinoma. Methods: The density of CD68+, CD163+, and MARCO+ macrophages was assessed by immunohistochemistry on tissue microarrays with primary tumors from a consecutive, retrospective cohort of 174 patients with treatment-naïve gastroesophageal adenocarcinoma. Total densities and infiltration in tumor nest (TN) were denoted as none/sparse (0), intermediate (1), or high (2). The impact on overall survival (OS) was examined by Kaplan–Meier analysis, log-rank test, and Cox proportional hazards modeling. Results: Increased infiltration of both CD68+ and CD163+, but not MARCO+, macrophages in TN was significantly associated with a stepwise reduced survival. Median OS for patients with none/sparse, intermediate, and high CD68+ TN infiltration was 4.4, 2.6, and 1.0 years, respectively. Median OS for patients with none/sparse, intermediate, and high CD163+ TN infiltration was 4.4, 2.2, and 1.1 years, respectively. High infiltration of CD68+ macrophages remained an independent prognostic factor in adjusted analysis (hazard ratio = 1.61, 95% confidence interval = 1.02–2.55, and p = 0.041). Conclusion: Infiltration of CD68+ and CD163+, but not MARCO+, macrophages is prognostic for OS in gastroesophageal adenocarcinoma. The relevance of this finding in clinical practice remains to be elucidated.
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Affiliation(s)
- Martin Jeremiasen
- Department of Clinical Sciences Lund, Surgery, Lund University, Lund, Sweden.,Skåne University Hospital, Lund, Sweden
| | - David Borg
- Skåne University Hospital, Lund, Sweden.,Department of Clinical Sciences Lund, Oncology and Therapeutic Pathology, Lund University, Lund, Sweden
| | - Charlotta Hedner
- Department of Clinical Sciences Lund, Oncology and Therapeutic Pathology, Lund University, Lund, Sweden
| | - Maria Svensson
- Department of Clinical Sciences Lund, Oncology and Therapeutic Pathology, Lund University, Lund, Sweden
| | - Björn Nodin
- Department of Clinical Sciences Lund, Oncology and Therapeutic Pathology, Lund University, Lund, Sweden
| | - Karin Leandersson
- Cancer Immunology, Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Jan Johansson
- Department of Clinical Sciences Lund, Surgery, Lund University, Lund, Sweden.,Skåne University Hospital, Lund, Sweden
| | - Karin Jirström
- Department of Clinical Sciences Lund, Oncology and Therapeutic Pathology, Lund University, Lund, Sweden
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31
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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: 262] [Impact Index Per Article: 52.4] [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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32
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The Macrophages-Microbiota Interplay in Colorectal Cancer (CRC)-Related Inflammation: Prognostic and Therapeutic Significance. Int J Mol Sci 2020; 21:ijms21186866. [PMID: 32962159 PMCID: PMC7558485 DOI: 10.3390/ijms21186866] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/15/2020] [Accepted: 09/16/2020] [Indexed: 02/07/2023] Open
Abstract
Tumor-associated macrophages (TAMs) are the main population of myeloid cells infiltrating solid tumors and the pivotal orchestrators of cancer-promoting inflammation. However, due to their exceptional plasticity, macrophages can be also key effector cells and powerful activators of adaptive anti-tumor immunity. This functional heterogeneity is emerging in human tumors, colorectal cancer (CRC) in particular, where the dynamic co-existence of different macrophage subtypes influences tumor development, outcome, and response to therapies. Intestinal macrophages are in close interaction with enteric microbiota, which contributes to carcinogenesis and affects treatment outcomes. This interplay may be particularly relevant in CRC, one of the most prevalent and lethal cancer types in the world. Therefore, both macrophages and intestinal microbiota are considered promising prognostic indicators and valuable targets for new therapeutic approaches. Here, we discuss the current understanding of the molecular circuits underlying the interplay between macrophages and microbiota in CRC development, progression, and response to both conventional therapies and immunotherapies.
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33
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Yang Z, Zhang M, Peng R, Liu J, Wang F, Li Y, Zhao Q, Liu J. The prognostic and clinicopathological value of tumor-associated macrophages in patients with colorectal cancer: a systematic review and meta-analysis. Int J Colorectal Dis 2020; 35:1651-1661. [PMID: 32666290 DOI: 10.1007/s00384-020-03686-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/03/2020] [Indexed: 02/06/2023]
Abstract
PURPOSE There is a growing literature on the significance of tumor-associated macrophages (TAMs) in colorectal cancer (CRC). However, the role of TAMs in predicting the prognosis of CRC remains controversial. The current study aims to determine the prognostic and clinicopathological value of different types and distribution of TAMs in CRC. METHODS A comprehensive literature search of PubMed, Embase, and Cochrane Library databases was conducted from the inception to 1 September 2019. The correlations of TAMs with overall survival (OS), disease-free survival (DFS), cancer-specific survival (CSS), and clinicopathological characteristics were analyzed. RESULTS A total of 5,575 patients from 29 studies were included in this meta-analysis. The pooled hazard ratios (HRs) indicated that high density of pan-macrophages in tumor invasive margin (IM) was associated with better OS (HR = 0.57, 95%CI = 0.38-0.85), DFS (HR = 0.32, 95%CI = 0.19-0.52), and CSS (HR = 0.56, 95%CI = 0.41-0.77). Moreover, the high density of pan-macrophages in tumor center (TC) was correlated with better DFS (HR = 0.66, 95%CI = 0.45-0.96). However, high expression of M2 macrophages in TC was associated with poor DFS (HR = 2.42, 95%CI = 1.45-4.07) and CSS (HR = 1.74, 95%CI = 1.24-2.44). High M2 macrophages density in IM was also associated with short DFS (HR = 2.81, 95%CI = 1.65-4.77). In addition, the results showed that high density of pan-macrophages in IM was associated with no tumor metastasis, while high M2 macrophages density in TC was correlated with poor tumor differentiation. CONCLUSION High Pan-TAMs density in IM has a positive effect on the prognosis of CRC patients, while high density M2 macrophage infiltration in TC is a strong indicator of poor prognosis.
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Affiliation(s)
- Zhenwei Yang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Mengna Zhang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Ruyi Peng
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Jialong Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Fan Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Yizhang Li
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Jing Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
- Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China.
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Perini MV, Dmello RS, Nero TL, Chand AL. Evaluating the benefits of renin-angiotensin system inhibitors as cancer treatments. Pharmacol Ther 2020; 211:107527. [PMID: 32173557 DOI: 10.1016/j.pharmthera.2020.107527] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 03/08/2020] [Indexed: 02/07/2023]
Abstract
G-protein-coupled receptors (GPCRs) are the largest and most diverse group of cellular membrane receptors identified and characterized. It is estimated that 30 to 50% of marketed drugs target these receptors. The angiotensin II receptor type 1 (AT1R) is a GPCR which signals in response to systemic alterations of the peptide hormone angiotensin II (AngII) in circulation. The enzyme responsible for converting AngI to AngII is the angiotensin-converting enzyme (ACE). Specific inhibitors for the AT1R (more commonly known as AT1R blockers or antagonists) and ACE are well characterized for their effects on the cardiovascular system. Combined with the extensive clinical data available on patient tolerance of AT1R blockers (ARBs) and ACE inhibitors (ACEIs), as well as their non-classical roles in cancer, the notion of repurposing this class of medications as cancer treatment(s) is explored in the current review. Given that AngII-dependent AT1R activity directly regulates angiogenesis, remodeling of vasculature, pro-inflammatory responses, stem cell programming and hematopoiesis, and electrolyte balance; the modulation of these processes with pharmacologically well characterized medications could present a valuable complementary treatment option for cancer patients.
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Affiliation(s)
- Marcos V Perini
- Department of Surgery, The University of Melbourne, and Austin Health, Heidelberg, VIC, Australia
| | - Rhynelle S Dmello
- Cancer and Inflammation Program, Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia
| | - Tracy L Nero
- Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Parkville, VIC, Australia
| | - Ashwini L Chand
- Cancer and Inflammation Program, Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia.
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35
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Tumor-associated macrophage infiltration and prognosis in colorectal cancer: systematic review and meta-analysis. Int J Colorectal Dis 2020; 35:1203-1210. [PMID: 32303831 DOI: 10.1007/s00384-020-03593-z] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/04/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) are key components of colorectal cancer (CRC) microenvironment, but their role in CRC prognosis is not fully defined. OBJECTIVE This study aimed to evaluate prognostic value of different types and distribution of TAMs in CRC. METHODS Total 27 studies with 6115 patients were searched from PubMed and Embase and analyzed to determine the association between TAMs, including distinct TAM subsets and infiltration location, and CRC survival. The prognostic impact of TAMs on CRC was further stratified by tumor type and mismatch repair system (MMR) status. RESULTS A pooled analysis indicated that high density of TAMs in CRC tissue was significantly associated with favorable 5-year overall survival (OS) but not with disease-free survival (DFS). CD 68+ TAM subset correlated with better 5-year OS, while neither CD68+NOS2+ M1 subset nor CD163+ M2 subset was correlated with 5-year OS. Increased CD68+ TAM infiltration in tumor stroma but not in tumor islet predicted improved 5-year OS. Stratification by tumor type and MMR status showed that in colon cancer or MMR-proficient CRC, elevated TAM density was associated with better 5-year OS. CONCLUSIONS High infiltration of CD68+ TAMs could be a favorable prognostic marker in CRC. Future therapies stimulating CD68+ TAM infiltration may be promising in CRC treatment.
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36
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Li X, Tang M. Exosomes released from M2 macrophages transfer miR-221-3p contributed to EOC progression through targeting CDKN1B. Cancer Med 2020; 9:5976-5988. [PMID: 32590883 PMCID: PMC7433826 DOI: 10.1002/cam4.3252] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 06/04/2020] [Accepted: 06/05/2020] [Indexed: 12/24/2022] Open
Abstract
In contrast to other solid tumors within the abdominal cavity, epithelial ovarian cancers (EOCs) tend to undergo peritoneal metastasis. Thus, the peritoneal immune microenvironment is crucial for EOC progression. Previous reports indicate that the main immune cells within the peritoneum are M2 macrophages, specifically tumor‐associated macrophages (TAMs). The communication between TAMs and tumor cells plays an important role in EOC development, and exosomes, acting as micro–message carriers, occupy an essential position in this process. Microarray analyses of exosomes revealed that miR‐221‐3p was enriched in M2 exosomes. Furthermore, miR‐221‐3p suppressed cyclin‐dependent kinase inhibitor 1B (CDKN1B) directly. Thus, miR‐221‐3p contributed to the proliferation and G1/S transition of EOC cells. Additionally, low levels of CDKN1B were associated with EOC progression and poor prognosis. These observations suggest that TAMs‐derived exosomal miR‐221‐3p acts as a regulator of EOC progression by targeting CDKN1B. The results of this study confirm that certain exosomal microRNAs may provide novel diagnostic biomarkers and therapeutic targets for EOC.
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Affiliation(s)
- Xiaoduan Li
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Meiling Tang
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
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37
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Guo L, Wang C, Qiu X, Pu X, Chang P. Colorectal Cancer Immune Infiltrates: Significance in Patient Prognosis and Immunotherapeutic Efficacy. Front Immunol 2020; 11:1052. [PMID: 32547556 PMCID: PMC7270196 DOI: 10.3389/fimmu.2020.01052] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 04/30/2020] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer occurrence and progression involve multiple aspects of host immune deficiencies. In these events, immune cells vary their phenotypes and functions over time, thus enabling the immune microenvironment to be “tumor-inhibiting” as well as “tumor-promoting” as a whole. Because of the association of tumoricidal T cell infiltration with favorable survival in cancer patients, the Immunoscore system was established. Critically, the tumoral Immunoscore serves as an indicator of CRC patient prognosis independent of patient TNM stage and suggests that patients with high Immunoscores in their tumors have prolonged survival in general. Accordingly, stratifications according to tumoral Immunoscores provide new insights into CRC in terms of comparing disease severity, forecasting disease progression, and making treatment decisions. An important application of this system will be to shed light on candidate selection in immunotherapy for CRC, because the T cells responsible for determining the Immunoscore serve as responders to immune checkpoint inhibitors. However, the Immunoscore system merely provides a standard procedure for identifying the tumoral infiltration of cytotoxic and memory T cells, while information concerning the survival and function of these cells is still absent. Moreover, other infiltrates, such as dendritic cells, macrophages, and B cells, can still influence CRC prognosis, implying that those might also influence the therapeutic efficacy of immune checkpoint inhibitors. On these bases, this review is designed to introduce the Immunoscore system by presenting its clinical significance and application in CRC.
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Affiliation(s)
- Liang Guo
- Department of Pathology, The First Hospital of Jilin University, Changchun, China
| | - Chuanlei Wang
- Department of Hepatobiliary Pancreatic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Xiang Qiu
- Department of Radiology, The First Hospital of Jilin University, Changchun, China
| | - Xiaoyu Pu
- Department of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun, China
| | - Pengyu Chang
- Department of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun, China.,Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun, China.,Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Department of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun, China
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38
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Lee YS, Song SJ, Hong HK, Oh BY, Lee WY, Cho YB. The FBW7-MCL-1 axis is key in M1 and M2 macrophage-related colon cancer cell progression: validating the immunotherapeutic value of targeting PI3Kγ. Exp Mol Med 2020; 52:815-831. [PMID: 32444799 PMCID: PMC7272616 DOI: 10.1038/s12276-020-0436-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 02/23/2020] [Accepted: 04/08/2020] [Indexed: 11/15/2022] Open
Abstract
Colorectal cancer is a devastating disease with a low 5-year survival rate. Recently, many researchers have studied the mechanisms of tumor progression related to the tumor microenvironment. Here, we addressed the prognostic value of tumor-associated macrophages (TAMs) using a total of 232 CRC patient tissue samples and investigated the mechanisms underlying TAM-related colon cancer progression with respect to PI3Kγ regulation using in vitro, in vivo, and ex vivo approaches. Patients with M2/M1 < 3 had significantly improved progression-free survival and overall survival compared with patients with M2/M1 > 3. M1 and M2 macrophages elicited opposite effects on colon cancer progression via the FBW7-MCL-1 axis. Blocking macrophage PI3Kγ had cytotoxic effects on colon cancer cells and inhibited epithelial–mesenchymal transition features by regulating the FBW7-MCL-1 axis. The results of this study suggest that macrophage PI3Kγ may be a promising target for immunotherapy in colon cancer. Drugs that target a specific subset of immune cells could render colorectal tumors more susceptible to immunological destruction by the host. The cellular composition of a tumor profoundly affects the odds of progression or survival, and some immune cell types can stall the antitumor response rather than strengthening it. Researchers led by Yong Beom Cho of Sungkyunkwan University, Seoul, South Korea, explored the impact of various subpopulations of macrophages, cells that help coordinate the immune counterattack against cancer. The researchers learned that the relative balance between M2 and M1 subtypes of macrophages correlates with colorectal cancer outcomes, patients with less M2 and more M1 activity generally faring better. They also uncovered a strategy for inhibiting M2 activity, which unleashes a more-aggressive response against the tumor and could thus offer a useful therapeutic approach.
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Affiliation(s)
- Yeo Song Lee
- Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Institute for Future Medicine Samsung Medical Center, Seoul, Republic of Korea
| | - Su Jeong Song
- Institute for Future Medicine Samsung Medical Center, Seoul, Republic of Korea
| | - Hye Kyung Hong
- Institute for Future Medicine Samsung Medical Center, Seoul, Republic of Korea
| | - Bo Young Oh
- Department of Colorectal Surgery, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea
| | - Woo Yong Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea
| | - Yong Beom Cho
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. .,Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea.
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Hand F, Ryan EJ, Harrington C, Durand M, Maguire D, O'Farrelly C, Hoti E, Geoghegan JG. Chemotherapy and repeat resection abrogate the prognostic value of neutrophil lymphocyte ratio in colorectal liver metastases. HPB (Oxford) 2020; 22:670-676. [PMID: 31570259 DOI: 10.1016/j.hpb.2019.09.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Revised: 08/30/2019] [Accepted: 09/08/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Evolution in surgical and oncological management of CRLM has called into question the utility of clinical risk scores. We sought to establish if neutrophil lymphocyte ratio (NLR) has a prognostic role in this patient cohort. METHODS From 2005 to 2015,379 hepatectomies were performed for CRLM, 322 underwent index hepatectomy, 57 s hepatectomies were performed. Clinicopathological data were obtained from a prospectively maintained database. Variables associated with longterm survival following index and second hepatectomy were identified by Cox regression analyses and reviewed along with 30-day post-operative morbidity and mortality. RESULTS Following index hepatectomy 1-,3-and 5-year survival was 90.7%, 68.1% and 48.6%. Major resection, positive margins and >5 tumours were negatively associated with survival. Those with elevated NLR(>5) had a median survival of 55 months, compared to 70 months with lower NLR(p = 0.027). Following neoadjuvant chemotherapy, no association between NLR and survival was demonstrated (p = 0.93). Furthermore, NLR >5 had no impact on prognosis following repeat hepatectomy. Tumour diameter >5 cm (p = 0.04) was the sole predictor of poorer survival (p = 0.049). CONCLUSION Despite elevated NLR correlating with shorter survival following index hepatectomy, this effect is negated by neoadjuvant chemotherapy and second hepatectomy for recurrent disease. This data would not support the use of NLR in the preoperative decision algorithm for patients with CRLM.
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Affiliation(s)
- Fiona Hand
- Department of Hepatobiliary and Liver Transplant Surgery, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland; School of Biochemistry & Immunology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland.
| | - Elizabeth J Ryan
- Centre for Colorectal Disease, School of Medicine, University College Dublin and St. Vincent's Hospital, Elm Park, Dublin 4, Ireland
| | - Cuan Harrington
- Department of Surgical Affairs, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Michael Durand
- Department of Hepatobiliary and Liver Transplant Surgery, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland
| | - Donal Maguire
- Department of Hepatobiliary and Liver Transplant Surgery, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland
| | - Cliona O'Farrelly
- School of Biochemistry & Immunology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland
| | - Emir Hoti
- Department of Hepatobiliary and Liver Transplant Surgery, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland
| | - Justin G Geoghegan
- Department of Hepatobiliary and Liver Transplant Surgery, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland
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40
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Pellizzari G, Bax HJ, Josephs DH, Gotovina J, Jensen-Jarolim E, Spicer JF, Karagiannis SN. Harnessing Therapeutic IgE Antibodies to Re-educate Macrophages against Cancer. Trends Mol Med 2020; 26:615-626. [PMID: 32470387 DOI: 10.1016/j.molmed.2020.03.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 03/05/2020] [Accepted: 03/09/2020] [Indexed: 02/06/2023]
Abstract
Currently, IgG is the only class of antibodies employed for cancer therapy. However, harnessing the unique biological properties of a different class ( e.g., IgE) could engender potent effector cell activation, and unleash previously untapped immune mechanisms against cancer. IgE antibodies are best known for pathogenic roles in allergic diseases and for protective effector functions against parasitic infestation, often mediated by IgE Fc receptor-expressing macrophages. Notably, IgE possess a very high affinity for cognate Fc receptors expressed by tumor-associated macrophages (TAMs). This paper reviews pre-clinical studies, which indicate control of cancer growth by tumor antigen-specific IgE that recruit and re-educate TAMs towards activated profiles. The clinical development harnessing the antitumor potential of recombinant IgE antibodies in cancer patients is also discussed.
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Affiliation(s)
- Giulia Pellizzari
- St. John's Institute of Dermatology, School of Basic and Medical Biosciences, Guy's Hospital, King's College London, London, UK
| | - Heather J Bax
- St. John's Institute of Dermatology, School of Basic and Medical Biosciences, Guy's Hospital, King's College London, London, UK; School of Cancer and Pharmaceutical Sciences, King's College London, Guy's Hospital, London, UK
| | - Debra H Josephs
- St. John's Institute of Dermatology, School of Basic and Medical Biosciences, Guy's Hospital, King's College London, London, UK; School of Cancer and Pharmaceutical Sciences, King's College London, Guy's Hospital, London, UK
| | - Jelena Gotovina
- Institute of Pathophysiology and Allergy Research, Medical University Vienna, Vienna, Austria; The Interuniversity Messerli Research Institute of the University of Veterinary Medicine Vienna, Medical University Vienna and University Vienna, Vienna, Austria
| | - Erika Jensen-Jarolim
- Institute of Pathophysiology and Allergy Research, Medical University Vienna, Vienna, Austria; The Interuniversity Messerli Research Institute of the University of Veterinary Medicine Vienna, Medical University Vienna and University Vienna, Vienna, Austria
| | - James F Spicer
- School of Cancer and Pharmaceutical Sciences, King's College London, Guy's Hospital, London, UK.
| | - Sophia N Karagiannis
- St. John's Institute of Dermatology, School of Basic and Medical Biosciences, Guy's Hospital, King's College London, London, UK.
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Zhang P, Shi L, Song L, Long Y, Yuan K, Ding W, Deng L. LncRNA CRNDE and lncRNA SNHG7 are Promising Biomarkers for Prognosis in Synchronous Colorectal Liver Metastasis Following Hepatectomy. Cancer Manag Res 2020; 12:1681-1692. [PMID: 32210611 PMCID: PMC7069563 DOI: 10.2147/cmar.s233147] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 12/20/2019] [Indexed: 01/03/2023] Open
Abstract
Purpose Synchronous colorectal liver metastasis (SCLM) had limited availability of tools to predict survival and tumor recurrence. LncRNA CRNDE and lncRNA SNHG7 have been proven to be closely related to cancer progression. However, the predictive value of lncRNA CRNDE and lncRNA SNHG7 in cancer prognosis is still unclear. The purpose of this study was to investigate whether lncRNA CRNDE and lncRNA SNHG7 could be used as promising biomarkers for prognosis prediction of SCLM patients who underwent hepatectomy. Methods The expression profile of lncRNA CRNDE and lncRNA SNHG7 in serum of SCLM patients was examined by qRT-PCR. The relationship between lncRNA expression and clinicopathological characteristics was analyzed. The Cox proportional-hazards regression model and Kaplan-Meier analysis were performed to analyze the association between lncRNA expression and overall survival (OS) and tumor recurrence of SCLM patients. Results Levels of lncRNA CRNDE and lncRNA SNHG7 in patients who underwent recurrence or death were significantly higher than that of patients with recurrence-free or survival (P<0.01). Both lncRNA CRNDE high level and lncRNA SNHG7 high level showed a significant correlation with differentiation of primary tumor, invasion depth of primary focus, lymph node metastases, number of liver metastases, and liver metastasis grade. High levels of lncRNA CRNDE or lncRNA SNHG7 predicted shorter recurrence time, shorter OS time, higher recurrence rate and lower OS rate. Furthermore, lncRNA CRNDE and lncRNA SNHG7 were independent risk factors for high recurrence and poor OS in SCLM underwent hepatectomy. Conclusion Taken together, lncRNA CRNDE and lncRNA SNHG7 could be promising biomarkers for prediction of OS and tumor recurrence in SCLM underwent hepatectomy.
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Affiliation(s)
- Peixian Zhang
- Department of Oncology, Yan'an Hospital of Kunming City & Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - Lan Shi
- Department of Oncology, Yan'an Hospital of Kunming City & Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - Linjing Song
- Department of Oncology, Yan'an Hospital of Kunming City & Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - Yi Long
- Department of Oncology, Yan'an Hospital of Kunming City & Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - Kehua Yuan
- Department of Oncology, Yan'an Hospital of Kunming City & Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - Wanbao Ding
- Department of Oncology, Yan'an Hospital of Kunming City & Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - Lei Deng
- Department of Oncology, Yan'an Hospital of Kunming City & Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan, People's Republic of China
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Promising Colorectal Cancer Biomarkers for Precision Prevention and Therapy. Cancers (Basel) 2019; 11:cancers11121932. [PMID: 31817090 PMCID: PMC6966638 DOI: 10.3390/cancers11121932] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 12/02/2019] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer (CRC) has been ranked as the third most prevalent cancer worldwide. Indeed, it represents 10.2% of all cancer cases. It is also the second most common cause of cancer mortality, and accounted for about 9.2% of all cancer deaths in 2018. Early detection together with a correct diagnosis and staging remains the most effective clinical strategy in terms of disease recovery. Thanks to advances in diagnostic techniques, and improvements of surgical adjuvant and palliative therapies, the mortality rate of CRC has decreased by more than 20% in the last decade. Cancer biomarkers for the early detection of CRC, its management, treatment and follow-up have contributed to the decrease in CRC mortality. Herein, we provide an overview of molecular biomarkers from tumor tissues and liquid biopsies that are approved for use in the CRC clinical setting for early detection, follow-up, and precision therapy, and of biomarkers that have not yet been officially validated and are, nowadays, under investigation.
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Zhao Y, Ge X, Xu X, Yu S, Wang J, Sun L. Prognostic value and clinicopathological roles of phenotypes of tumour-associated macrophages in colorectal cancer. J Cancer Res Clin Oncol 2019; 145:3005-3019. [PMID: 31650222 DOI: 10.1007/s00432-019-03041-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 09/28/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND The role of tumour-associated macrophages (TAMs) in predicting the prognosis of colorectal cancer (CRC) remains controversial. This is especially so because the prognostic significance and clinicopathological relevance of different subtypes of TAMs in the immune microenvironment of CRC have not yet been established. OBJECTIVE To assess the clinicopathological and prognostic value of pan-macrophages, M1-macrophages or M2-macrophages in patients with CRC. METHODS Comprehensive searched on the Medline/PubMed, Web of Science (WoS) and Google Scholar databases was conducted to identify relevant studies published up to April 2019. The association between overall survival (OS), cancer-specific survival (CSS) or disease-free survival (DFS) and TAMs was analysed by meta-analysis. RESULTS A total of 3749 patients from 17 studies were included. The pooled hazard ratios (HRs) indicated that high-density pan-macrophages improved OS (HR 0.67, P = 0.02). The pooled HR for M2-macrophages showed that high M2-macrophages infiltration was significantly associated with shorter OS (HR 2.93, P < 0.0001) and DFS (HR 2.04, P = 0.02). The pooled odds ratios (ORs) revealed that high-density TAMs was associated with high CD8+ T cell infiltration (OR 2.04, P = 0.007), no distant metastasis (NDM) (OR 0.38, P < 0.0001), microsatellite instability-high (MSI-H) (OR 0.38, P = 0.001), no lymph node metastasis (NLNM) (OR 0.54, P = 0.0002) and non-mucinous cancer (OR 0.39, P < 0.00001). CONCLUSIONS Unlike other solid tumours, high-density CD68+ macrophage infiltration can be a good prognostic marker for CRC. However, when macrophages act as targets of combination therapy in CRC treatment, this might be more effective for CRC patients with high CD8+ T cell infiltrate, NDM, MSI-H, NLNM and non-mucinous cancer.
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Affiliation(s)
- Yamei Zhao
- Department of Colorectal Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, People's Republic of China
| | - Xiaoxu Ge
- Department of Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China
| | - Xiaoming Xu
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China
| | - Shaojun Yu
- Department of Colorectal Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, People's Republic of China
| | - Jian Wang
- Department of Colorectal Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, People's Republic of China.
| | - Lifeng Sun
- Department of Colorectal Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, People's Republic of China.
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Donadon M, Cortese N, Marchesi F, Cimino M, Mantovani A, Torzilli G. Hepatobiliary surgeons meet immunologists: the case of colorectal liver metastases patients. Hepatobiliary Surg Nutr 2019; 8:370-377. [PMID: 31489306 PMCID: PMC6700021 DOI: 10.21037/hbsn.2019.03.06] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 03/05/2019] [Indexed: 12/14/2022]
Abstract
The burgeoning field of cancer immunology demands a change in the paradigm of cancer patient management. The understanding of the course of a given malignant disease should also include the host immune system as one of the key factors in determining the patient's prognosis. Surgical and medical oncologists need to understand the basic and advanced applications of immunotherapies, which are rapidly evolving, and are nowadays an integral part of the armamentarium for the treatment of cancer patients. In the present work, we review the current knowledge concerning the immune landscape of colorectal cancer (CRC) patients with liver metastases, as recently discovered.
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Affiliation(s)
- Matteo Donadon
- Department of Hepatobiliary and General Surgery, Humanitas University, Pieve Emanuele, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Nina Cortese
- Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Federica Marchesi
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Matteo Cimino
- Department of Hepatobiliary and General Surgery, Humanitas University, Pieve Emanuele, Italy
| | - Alberto Mantovani
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
- The William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Guido Torzilli
- Department of Hepatobiliary and General Surgery, Humanitas University, Pieve Emanuele, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
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45
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Ge P, Wang W, Li L, Zhang G, Gao Z, Tang Z, Dang X, Wu Y. Profiles of immune cell infiltration and immune-related genes in the tumor microenvironment of colorectal cancer. Biomed Pharmacother 2019; 118:109228. [PMID: 31351430 DOI: 10.1016/j.biopha.2019.109228] [Citation(s) in RCA: 162] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 07/07/2019] [Accepted: 07/15/2019] [Indexed: 12/16/2022] Open
Abstract
PURPOSE tumor-infiltrating immune cells are highly relevant to the progression and prognosis of colorectal cancer (CRC). The aim of this study is to explore the immune cells and immune-related gene expression in tumor microenvironment of CRC. METHODS CIBERSORT, a deconvolution algorithm, was used to analyze the infiltration of 22 immune cell types in the tumor microenvironment and immune-related gene expression in 404 CRC and 40 adjacent non-tumorous tissues. RESULTS a wide heterogeneity of immune cells among different paired tissues and in tumor stages was uncovered. M0 macrophages, M1 macrophages and CD4 memory activated T cells were infiltrated significantly more in CRC compared with normal tissues in both TCGA and GEO cohorts. CRC with T1-2 tumor stage showed increased CD4 memory activated T cells compared with T3-4 tumors. M0 macrophages were the highest in stage N1 tumors. Significant immune-related genes were identified to build prognostic models by Cox regression analysis. The concordance index of the prognostic model for TNM stage I-II was 0.69, and 0.71 for stage III-IV. The AUC values for 1-, 3-, and 5-year survivals were 0.674, 0.773, 0.812 for TNM stage I-II, respectively, and 0.764, 0.782, 0.803 for stage III-IV, respectively. CONCLUSION these results could assist clinicians in selecting targets for immunotherapies and individualize treatment strategies for patients with CRC.
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Affiliation(s)
- Penglei Ge
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan Province, China.
| | - Weiwei Wang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan Province, China
| | - Lin Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan Province, China
| | - Gong Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan Province, China
| | - Zhiqiang Gao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan Province, China
| | - Zhe Tang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan Province, China
| | - Xiaowei Dang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan Province, China
| | - Yang Wu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan Province, China.
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Freire Valls A, Knipper K, Giannakouri E, Sarachaga V, Hinterkopf S, Wuehrl M, Shen Y, Radhakrishnan P, Klose J, Ulrich A, Schneider M, Augustin HG, Ruiz de Almodovar C, Schmidt T. VEGFR1 + Metastasis-Associated Macrophages Contribute to Metastatic Angiogenesis and Influence Colorectal Cancer Patient Outcome. Clin Cancer Res 2019; 25:5674-5685. [PMID: 31239322 DOI: 10.1158/1078-0432.ccr-18-2123] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 05/14/2019] [Accepted: 06/20/2019] [Indexed: 11/16/2022]
Abstract
PURPOSE To investigate the clinical relevance of macrophages in liver metastasis of colorectal cancer and their influence on angiogenesis and patient survival. Moreover to evaluate specific blood monocytes as markers of disease recurrence.Experimental design: In a mouse model with spontaneous liver metastasis, the angiogenic characteristics of tumor- and metastasis (MAM)-associated macrophages were evaluated. Macrophages and the vasculature from 130 primary tumor (pTU) and 123 patients with liver metastasis were assessed. In vivo and in human samples, the clinical relevance of macrophage VEGFR1 expression was analyzed. Blood samples from patients (n = 157, 80 pTU and 77 liver metastasis) were analyzed for assessing VEGFR1-positive (VEGFR1+) cells as suitable biomarkers of disease recurrence. RESULTS The number of macrophages positively correlated with vascularization in metastasis. Both in the murine model as well as in primary isolated human cells, a subpopulation of MAMs expressing VEGFR1 were found highly angiogenic. While VEGFR1 expression in pTU patients did not predict prognosis; high percentage of VEGFR1+ cells in liver metastasis was associated with worse patient outcome. Interestingly, VEGFR1+-circulating monocytes in blood samples from patients with liver metastasis not only predicted progression but also site of recurrence. CONCLUSIONS Our findings identify a new subset of proangiogenic VEGFR1+ MAMs in colorectal cancer that support metastatic growth and may become a liquid biomarker to predict disease recurrence in the liver.
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Affiliation(s)
- Aida Freire Valls
- Department of General, Visceral, and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany.,Biochemistry Center Heidelberg (BZH), Heidelberg University, Heidelberg, Germany
| | - Karl Knipper
- Department of General, Visceral, and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany
| | - Evangelia Giannakouri
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ), Heidelberg, Germany.,European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - Víctor Sarachaga
- Biochemistry Center Heidelberg (BZH), Heidelberg University, Heidelberg, Germany
| | - Sascha Hinterkopf
- Department of General, Visceral, and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany
| | - Michael Wuehrl
- Department of General, Visceral, and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany
| | - Ying Shen
- Department of General, Visceral, and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany
| | - Praveenkumar Radhakrishnan
- Department of General, Visceral, and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany
| | - Johannes Klose
- Department of General, Visceral, and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany
| | - Alexis Ulrich
- Department of General, Visceral, and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany
| | - Martin Schneider
- Department of General, Visceral, and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany
| | - Hellmut G Augustin
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ), Heidelberg, Germany.,European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - Carmen Ruiz de Almodovar
- Biochemistry Center Heidelberg (BZH), Heidelberg University, Heidelberg, Germany.,European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.,Institute for Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Thomas Schmidt
- Department of General, Visceral, and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany.
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Cortese N, Soldani C, Franceschini B, Barbagallo M, Marchesi F, Torzilli G, Donadon M. Macrophages in Colorectal Cancer Liver Metastases. Cancers (Basel) 2019; 11:633. [PMID: 31067629 PMCID: PMC6562719 DOI: 10.3390/cancers11050633] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 05/02/2019] [Accepted: 05/03/2019] [Indexed: 12/14/2022] Open
Abstract
Tumor-associated macrophages (TAMs) provide a nurturing microenvironment for metastasis and are concomitantly key determinants of the efficacy of anticancer strategies. TAM represent an extremely heterogeneous population in terms of cell morphology, functions, and tissue localization. Colorectal liver metastases (CLM) display a high heterogeneity, responsible for a wide array of clinical presentations and responsiveness to treatments. In the era of precision medicine, there is a critical need of reliable prognostic markers to improve patient stratification, and, for their predominance in metastatic tissues, TAMs are emerging as promising candidates.
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Affiliation(s)
- Nina Cortese
- Department of Immunology and Inflammation, Humanitas Clinical and Research Center, 20089 Rozzano, Italy.
| | - Cristiana Soldani
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, 20089 Rozzano, Italy.
| | - Barbara Franceschini
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, 20089 Rozzano, Italy.
| | - Marialuisa Barbagallo
- Department of Immunology and Inflammation, Humanitas Clinical and Research Center, 20089 Rozzano, Italy.
| | - Federica Marchesi
- Department of Immunology and Inflammation, Humanitas Clinical and Research Center, 20089 Rozzano, Italy.
- Department of Biotechnology and Translational Medicine, University of Milan, 20090 Segrate, Italy.
| | - Guido Torzilli
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, 20089 Rozzano, Italy.
- Department of Biomedical Science, Humanitas University, 20089 Rozzano, Italy.
| | - Matteo Donadon
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, 20089 Rozzano, Italy.
- Department of Biomedical Science, Humanitas University, 20089 Rozzano, Italy.
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48
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Hof J, Kok K, Sijmons RH, de Jong KP. Systematic Review of the Prognostic Role of the Immune System After Surgery of Colorectal Liver Metastases. Front Oncol 2019; 9:148. [PMID: 30941301 PMCID: PMC6433783 DOI: 10.3389/fonc.2019.00148] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Accepted: 02/21/2019] [Indexed: 12/11/2022] Open
Abstract
Background: The current prognostication of patient survival after surgery for colorectal liver metastases is based on clinical characteristics, but low accuracy makes it difficult to guide treatment for the individual patient. Rapidly evolving technologies have led to the expectation that biomarkers will be able to outperform the current clinical scoring systems and provide more effective personalised treatment. Two main topics prevail in cancer treatment, namely the role of the immune system and the prediction and prognostication by application of high-throughput methodology. The aim of this review is to examine the evidence for prognostic immunological and molecular markers studied in tumour tissue obtained at surgical resection for colorectal liver metastases. Methods: First we analysed immunophenotypical protein markers, that are mainly studied by immunohistochemistry. Second, we review molecular markers by analysing high-throughput studies on tumour mRNA and microRNA expression. Results: CD3, CD4, and CD8 are the most frequently studied protein markers. High intra-tumoural CD3+ T cell infiltration and low CXCR4 expression have the best association with favourable patient survival. Studies that analysed microRNA or mRNA expression data showed very little overlap in prognostic genes. Conclusions: Patient prognostication after surgery for colorectal liver metastases by analysing the immune system remains difficult. Current data are based on diverse and heterogeneous patient populations which prohibits drawing firm conclusions.
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Affiliation(s)
- Joost Hof
- Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.,Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Klaas Kok
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Rolf H Sijmons
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Koert P de Jong
- Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
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Ihling C, Naughton B, Zhang Y, Rolfe PA, Frick-Krieger E, Terracciano LM, Dussault I. Observational Study of PD-L1, TGF-β, and Immune Cell Infiltrates in Hepatocellular Carcinoma. Front Med (Lausanne) 2019; 6:15. [PMID: 30800658 PMCID: PMC6375852 DOI: 10.3389/fmed.2019.00015] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 01/17/2019] [Indexed: 12/14/2022] Open
Abstract
Introduction: Hepatocellular carcinoma (HCC) typically develops in cirrhotic livers, with increased programed death ligand 1 (PD-L1) and transforming growth factor beta (TGF-β) activity implicated in immunosuppression. Methods: In an observational study of HCC liver samples, we determined the incidence of PD-L1 and immune cell (IC) infiltrates, and signs of TGF-β activity. HCCs were characterized by the incidence and distribution of PD-L1+ cells, and CD8+, CD68+, and FoxP3+ infiltrating ICs in HCC and surrounding liver. Gene expression signatures (GESs) associated with TGF-β activity and ICs were evaluated by RNAseq. Results: In non-neoplastic cirrhotic and non-cirrhotic liver, PD-L1 occurred on sinusoidal lining cells (mostly Kupffer cells), endothelial cells and ICs. In HCC, PD-L1+ tumor cells were rare. Most PD-L1+ cells were identified as ICs. CD8+, CD68+, and FoxP3+ ICs were associated with HCC, particularly in the invasive margin. CD8+ cell incidence correlated with PD-L1+ cells, consistent with PD-L1 being upregulated in response to pre-existing cytotoxic T-lymphocyte activity. TGFB1 mRNA levels and TGF-β activation GES correlated with the strength of the tumor-associated macrophage GES. Conclusion: Inhibition of PD-L1+ ICs and TGF-β activity and their respective immunomodulatory pathways may contribute to antitumor effects in HCC.
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Affiliation(s)
- Christian Ihling
- Global Clinical Biomarkers & Companion Diagnostics, Merck KGaA, Darmstadt, Germany
| | - Bartholomew Naughton
- Quantitative Pharmacology and Drug Disposition, EMD Serono, Inc., Billerica, MA, United States
| | - Yue Zhang
- Clinical Biomarkers & Companion Diagnostics Biopharma, EMD Serono, Inc., Billerica, MA, United States
| | - P Alexander Rolfe
- Quantitative Pharmacology and Drug Disposition, EMD Serono, Inc., Billerica, MA, United States
| | | | - Luigi M Terracciano
- Molecular Pathology Division, Institute of Pathology, University Hospital, Basel, Switzerland
| | - Isabelle Dussault
- Clinical Biomarkers & Companion Diagnostics Biopharma, EMD Serono, Inc., Billerica, MA, United States
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50
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Lazarus J, Maj T, Smith JJ, Perusina Lanfranca M, Rao A, D’Angelica MI, Delrosario L, Girgis A, Schukow C, Shia J, Kryczek I, Shi J, Wasserman I, Crawford H, Nathan H, Pasca Di Magliano M, Zou W, Frankel TL. Spatial and phenotypic immune profiling of metastatic colon cancer. JCI Insight 2018; 3:e121932. [PMID: 30429368 PMCID: PMC6302940 DOI: 10.1172/jci.insight.121932] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 10/11/2018] [Indexed: 12/14/2022] Open
Abstract
Paramount to the efficacy of immune checkpoint inhibitors is proper selection of patients with adequate tumor immunogenicity and a robust but suppressed immune infiltrate. In colon cancer, immune-based therapies are approved for patients with DNA mismatch repair (MMR) deficiencies, in whom accumulation of genetic mutations results in increased neoantigen expression, triggering an immune response that is suppressed by the PD-L1/PD-1 pathway. Here, we report that characterization of the microenvironment of MMR-deficient metastatic colorectal cancer using multiplex fluorescent immunohistochemistry (mfIHC) identified increased infiltration of cytotoxic T lymphocytes (CTLs), which were more often engaged with epithelial cells (ECs) and improved overall survival. A subset of patients with intact MMR but a similar immune microenvironment to MMR-deficient patients was identified and found to universally express high levels of PD-L1, suggesting that they may represent a currently untreated, checkpoint inhibitor-responsive population. Further, PD-L1 expression on antigen-presenting cells (APCs) in the tumor microenvironment (TME) resulted in impaired CTL/EC engagement and enhanced infiltration and engagement of Tregs. Characterization of the TME by mfIHC highlights the interconnection between immunity and immunosuppression in metastatic colon cancer and may better stratify patients for receipt of immunotherapies.
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Affiliation(s)
- Jenny Lazarus
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Tomasz Maj
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - J. Joshua Smith
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | | | - Arvind Rao
- Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA
| | - Michael I. D’Angelica
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | | | - Alexander Girgis
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Casey Schukow
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Jinru Shia
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Ilona Kryczek
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | | | - Isaac Wasserman
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Howard Crawford
- Department of Molecular and Cellular Physiology, University of Michigan, Ann Arbor, Michigan, USA
| | - Hari Nathan
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | | | - Weiping Zou
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
- Department of Pathology and
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