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Mathiesen H, Juul-Madsen K, Tramm T, Vorup-Jensen T, Møller HJ, Etzerodt A, Andersen MN. Prognostic value of CD163 + macrophages in solid tumor malignancies: A scoping review. Immunol Lett 2025; 272:106970. [PMID: 39778658 DOI: 10.1016/j.imlet.2025.106970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 12/19/2024] [Accepted: 01/02/2025] [Indexed: 01/11/2025]
Abstract
Tumor-associated macrophages (TAMs) play crucial roles in development and progression of malignant diseases. Notably, CD163+ TAMs likely perform specific pro-tumorigenic functions, suggesting that this subset may serve as both prognostic biomarkers and targets for future anti-cancer therapy. We conducted a scoping review to map the current knowledge on the prognostic role of CD163+ TAMs in the five most lethal cancers worldwide: Lung, colorectal, gastric, liver, and breast cancer. For all cancer types, most studies showed that high tumoral presence of CD163+ cells was associated with poor patient outcome, and this association was more frequently observed when CD163+ cells were measured at the tumor periphery compared to more central parts of the tumor. These results support that CD163+ TAMs represent a biomarker of poor patient outcome across a variety of solid tumors, and highlight the relevance of further investigations of CD163+ TAMs as targets of future immunotherapies.
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Affiliation(s)
- Henriette Mathiesen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Hematology, Aarhus University Hospital, Aarhus, Denmark
| | - Kristian Juul-Madsen
- Department of Biomedicine, Aarhus University, Aarhus, Denmark; Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
| | - Trine Tramm
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Holger Jon Møller
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Anders Etzerodt
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Morten Nørgaard Andersen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Hematology, Aarhus University Hospital, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
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2
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Tatsuno R, Komohara Y, Pan C, Kawasaki T, Enomoto A, Jubashi T, Kono H, Wako M, Ashizawa T, Haro H, Ichikawa J. Surface Markers and Chemokines/Cytokines of Tumor-Associated Macrophages in Osteosarcoma and Other Carcinoma Microenviornments-Contradictions and Comparisons. Cancers (Basel) 2024; 16:2801. [PMID: 39199574 PMCID: PMC11353089 DOI: 10.3390/cancers16162801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 08/01/2024] [Accepted: 08/07/2024] [Indexed: 09/01/2024] Open
Abstract
Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Prognosis is improving with advances in multidisciplinary treatment strategies, but the development of new anticancer agents has not, and improvement in prognosis for patients with pulmonary metastases has stalled. In recent years, the tumor microenvironment (TME) has gained attention as a therapeutic target for cancer. The immune component of OS TME consists mainly of tumor-associated macrophages (TAMs). They exhibit remarkable plasticity, and their phenotype is influenced by the TME. In general, surface markers such as CD68 and CD80 show anti-tumor effects, while CD163 and CD204 show tumor-promoting effects. Surface markers have potential value as diagnostic and prognostic biomarkers. The cytokines and chemokines produced by TAMs promote tumor growth and metastasis. However, the role of TAMs in OS remains unclear to date. In this review, we describe the role of TAMs in OS by focusing on TAM surface markers and the TAM-produced cytokines and chemokines in the TME, and by comparing their behaviors in other carcinomas. We found contrary results from different studies. These findings highlight the urgency for further research in this field to improve the stalled OS prognosis percentages.
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Affiliation(s)
- Rikito Tatsuno
- Department of Orthopaedic Surgery, University of Yamanashi, Yamanashi 400-0016, Japan; (R.T.); (T.J.); (H.K.); (M.W.); (T.A.); (H.H.)
| | - Yoshihiro Komohara
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8555, Japan; (Y.K.); (C.P.)
| | - Cheng Pan
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8555, Japan; (Y.K.); (C.P.)
| | - Tomonori Kawasaki
- Department of Pathology, Saitama Medical University International Medical Center, Saitama 350-1298, Japan;
| | - Atsushi Enomoto
- Department of Pathology, Graduate School of Medicine, Nagoya University, Nagoya 464-8601, Japan;
| | - Takahiro Jubashi
- Department of Orthopaedic Surgery, University of Yamanashi, Yamanashi 400-0016, Japan; (R.T.); (T.J.); (H.K.); (M.W.); (T.A.); (H.H.)
| | - Hiroyuki Kono
- Department of Orthopaedic Surgery, University of Yamanashi, Yamanashi 400-0016, Japan; (R.T.); (T.J.); (H.K.); (M.W.); (T.A.); (H.H.)
| | - Masanori Wako
- Department of Orthopaedic Surgery, University of Yamanashi, Yamanashi 400-0016, Japan; (R.T.); (T.J.); (H.K.); (M.W.); (T.A.); (H.H.)
| | - Tomoyuki Ashizawa
- Department of Orthopaedic Surgery, University of Yamanashi, Yamanashi 400-0016, Japan; (R.T.); (T.J.); (H.K.); (M.W.); (T.A.); (H.H.)
| | - Hirotaka Haro
- Department of Orthopaedic Surgery, University of Yamanashi, Yamanashi 400-0016, Japan; (R.T.); (T.J.); (H.K.); (M.W.); (T.A.); (H.H.)
| | - Jiro Ichikawa
- Department of Orthopaedic Surgery, University of Yamanashi, Yamanashi 400-0016, Japan; (R.T.); (T.J.); (H.K.); (M.W.); (T.A.); (H.H.)
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Debatin NF, Bady E, Mandelkow T, Huang Z, Lurati MCJ, Raedler JB, Müller JH, Vettorazzi E, Plage H, Samtleben H, Klatte T, Hofbauer S, Elezkurtaj S, Furlano K, Weinberger S, Giacomo Bruch P, Horst D, Roßner F, Schallenberg S, Marx AH, Fisch M, Rink M, Slojewski M, Kaczmarek K, Ecke TH, Hallmann S, Koch S, Adamini N, Lennartz M, Minner S, Simon R, Sauter G, Zecha H, Schlomm T, Blessin NC. Prognostic Impact and Spatial Interplay of Immune Cells in Urothelial Cancer. Eur Urol 2024; 86:42-51. [PMID: 38383257 DOI: 10.1016/j.eururo.2024.01.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 12/01/2023] [Accepted: 01/29/2024] [Indexed: 02/23/2024]
Abstract
BACKGROUND AND OBJECTIVE Quantity and the spatial relationship of specific immune cell types can provide prognostic information in bladder cancer. The objective of the study was to characterize the spatial interplay and prognostic role of different immune cell subpopulations in bladder cancer. METHODS A total of 2463 urothelial bladder carcinomas were immunostained with 21 antibodies using BLEACH&STAIN multiplex fluorescence immunohistochemistry in a tissue microarray format and analyzed using a framework of neuronal networks for an image analysis. Spatial immune parameters were compared with histopathological parameters and overall survival data. KEY FINDINGS AND LIMITATIONS The identification of > 300 different immune cell subpopulations and the characterization of their spatial relationship resulted in numerous spatial interaction patterns. Thirty-nine immune parameters showed prognostic significance in univariate analyses, of which 16 were independent from pT, pN, and histological grade in muscle-invasive bladder cancer. Among all these parameters, the strongest association with prolonged overall survival was identified for intraepithelial CD8+ cytotoxic T cells (time-dependent area under receiver operating characteristic curve [AUC]: 0.70), while stromal CD8+ T cells were less relevant (AUC: 0.65). A favorable prognosis of inflamed cancers with high levels of "exhaustion markers" suggests that TIM3, PD-L1, PD-1, and CTLA-4 on immune cells do not hinder antitumoral immune response in tumors rich of tumor infiltrating immune cells. CONCLUSIONS AND CLINICAL IMPLICATIONS The density of intraepithelial CD8+ T cells was the strongest prognostic feature in muscle-invasive bladder cancer. Given that tumor cell killing by CD8+ cytotoxic T lymphocytes through direct cell-to-cell-contacts represents the "terminal end route" of antitumor immunity, the quantity of "tumor cell adjacent CD8+ T cells" may constitute a surrogate for the efficiency of cancer recognition by the immune system that can be measured straightaway in routine pathology as the CD8 labeling index. PATIENT SUMMARY Quantification of intraepithelial CD8+ T cells, the strongest prognosticfeature identified in muscle-invasive bladder cancer, can easily be assessed by brightfield immunohistochemistry and is therefore "ready to use" for routine pathology.
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Affiliation(s)
- Nicolaus F Debatin
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Elena Bady
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tim Mandelkow
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Zhihao Huang
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Magalie C J Lurati
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jonas B Raedler
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; College of Arts and Sciences, Boston University, Boston, MA, USA
| | - Jan H Müller
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eik Vettorazzi
- Department of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Henning Plage
- Department of Urology, Charité Berlin, Berlin, Germany
| | - Henrik Samtleben
- Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany
| | - Tobias Klatte
- Department of Urology, Charité Berlin, Berlin, Germany; Department of Urology, Helios Hospital Bad Saarow, Bad Saarow, Germany
| | | | | | - Kira Furlano
- Department of Urology, Charité Berlin, Berlin, Germany
| | | | | | - David Horst
- Institute of Pathology, Charité Berlin, Berlin, Germany
| | | | | | - Andreas H Marx
- Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany
| | - Margit Fisch
- Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Rink
- Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marcin Slojewski
- Department of Urology, University Hospital Stettin, Stettin, Poland
| | | | - Thorsten H Ecke
- Department of Urology, Charité Berlin, Berlin, Germany; Department of Urology, Helios Hospital Bad Saarow, Bad Saarow, Germany
| | - Steffen Hallmann
- Department of Urology, Helios Hospital Bad Saarow, Bad Saarow, Germany
| | - Stefan Koch
- Department of Pathology, Helios Hospital Bad Saarow, Bad Saarow, Germany
| | - Nico Adamini
- Department of Urology, Albertinen Hospital, Hamburg, Germany
| | - Maximilian Lennartz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sarah Minner
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Henrik Zecha
- Department of Urology, Albertinen Hospital, Hamburg, Germany
| | | | - Niclas C Blessin
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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Bos J, Groen-van Schooten TS, Brugman CP, Jamaludin FS, van Laarhoven HWM, Derks S. The tumor immune composition of mismatch repair deficient and Epstein-Barr virus-positive gastric cancer: A systematic review. Cancer Treat Rev 2024; 127:102737. [PMID: 38669788 DOI: 10.1016/j.ctrv.2024.102737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 04/16/2024] [Accepted: 04/19/2024] [Indexed: 04/28/2024]
Abstract
BACKGROUND Gastric cancer (GC), known for its unfavorable prognosis, has been classified in four distinct molecular subtypes. These subtypes not only exhibit differences in their genome and transcriptome but also in the composition of their tumor immune microenvironment. The microsatellite instable (MSI) and Epstein-Barr virus (EBV) positive GC subtypes show clear clinical benefits from immune checkpoint blockade, likely due to a neoantigen-driven and virus-driven antitumor immune response and high expression of immune checkpoint molecule PD-L1. However, even within these subtypes response to checkpoint inhibition is variable, which is potentially related to heterogeneity in the tumor immune microenvironment (TIME) and expression of co-inhibitory molecules. We conducted a systematic review to outline the current knowledge about the immunological features on the TIME of MSI and EBV + GCs. METHODS A systematic search was performed in PubMed, EMBASE and Cochrane Library. All articles from the year 1990 and onwards addressing immune features of gastric adenocarcinoma were reviewed and included based on predefined in- and exclusion criteria. RESULTS In total 5962 records were screened, of which 139 were included that reported immunological data on molecular GC subtypes. MSI and EBV + GCs were reported to have a more inflamed TIME compared to non-MSI and EBV- GC subtypes. Compared to microsatellite stable (MSS) tumors, MSI tumors were characterized by higher numbers of CD8 + and FoxP3 + T cells, and tumor infiltrating pro- and anti-inflammatory macrophages. HLA-deficiency was most common in MSI tumors compared to other molecular GC subtypes and associated with lower T and B cell infiltrates compared to HLA-proficient tumors. EBV + was associated with a high number of CD8 + T cells, Tregs, NK cells and macrophages. Expression of PD-L1, CTLA-4, Granzyme A and B, Perforin and interferon-gamma was enriched in EBV + tumors. Overall, MSI tumors harbored a more heterogeneous TIME in terms of immune cell composition and immune checkpoints compared to the EBV + tumors. DISCUSSION AND CONCLUSION MSI and EBV + GCs are highly Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review and Evidence Integration.; 2019pro-inflammatory immune cell populations. Although studies on the direct comparison of EBV + and MSI tumors are limited, EBV + tumors show less intra-subgroup heterogeneity compared to MSI tumors. More studies are needed to identify how Intra-subgroup heterogeneity impacts response to immunotherapy efficacy.
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Affiliation(s)
- J Bos
- Amsterdam UMC Location University of Amsterdam, Department of Medical Oncology, Meibergdreef 9, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands
| | - T S Groen-van Schooten
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Medical Oncology, De Boelelaan 1117, Amsterdam, the Netherlands
| | - C P Brugman
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Medical Oncology, De Boelelaan 1117, Amsterdam, the Netherlands
| | - F S Jamaludin
- Amsterdam UMC Location University of Amsterdam, Medical Library AMC, Meibergdreef 9, Amsterdam, the Netherlands
| | - H W M van Laarhoven
- Amsterdam UMC Location University of Amsterdam, Department of Medical Oncology, Meibergdreef 9, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands
| | - S Derks
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Medical Oncology, De Boelelaan 1117, Amsterdam, the Netherlands.
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5
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Sharma N, Panigrahi R, Pradhan P, Parida S, Sahoo SR. Expression of CD68+ Tumor associated macrophages in relation to β-catenin in carcinoma stomach. INDIAN J PATHOL MICR 2024; 67:15-20. [PMID: 38358183 DOI: 10.4103/ijpm.ijpm_535_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2024] Open
Abstract
Background With no unified system for tumor associated macrophages (TAMs) density assessment, limited information is available on their relationship with β-catenin expression. Aim To evaluate the density of CD68+ TAMs in gastric adenocarcinoma samples by immunohistochemistry and correlate it with grade, stage, invasion, and beta-catenin. Designs and Settings Formalin fixed paraffin embedded (FFPE) blocks from gastrectomy specimens of proven gastric adenocarcinoma were prospectively and retrospectively were studied over a period of two years. Materials and Methods Immunohistochemistry with CD68 and β-catenin was performed. TAM density was qualitatively compared in "tumor" versus "stroma" and "tumor" versus "non-tumor" regions. Quantitative CD68+ TAM density was assessed using different methods and compared. Cases were classified as high and low TAM based on the median value and correlated with histologic type, location, grade, stage and β-catenin expression pattern. Statistical Analysis Spearman's rank correlation test was used to compare the different methods of TAM density evaluation. The categorical variables were studied using Pearson's Chi-square or Fisher's exact test. CD68+ TAM density and β-catenin expression were correlated by analysis of variance. A P value ≤ 0.05 was taken as statistically significant. Results The CD68+ TAMs in the "tumor" versus "non-tumor" area (p = 0.34) and "tumor" versus "stroma distribution" (p = 0.81) did not show any statistical significance. All methods of TAM density were found to be comparable. High TAM group is significantly associated with lymphovascular invasion, tumor depth, lymph node metastasis, and abnormal β-catenin expression. Conclusion TAMs density plays an important role in the tumor stage. Macrophages may possibly induce gastric cancer invasiveness by activating β-catenin pathway.
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Affiliation(s)
- Nikhil Sharma
- Department of Pathology, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | - Ranjita Panigrahi
- Department of Pathology, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | - Prita Pradhan
- Department of Pathology, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | - Sabyasachi Parida
- Department of Surgical Oncology, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | - Saroj R Sahoo
- Department of Surgical Oncology, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India
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Li J, Sun J, Zeng Z, Liu Z, Ma M, Zheng Z, He Y, Kang W. Tumour-associated macrophages in gastric cancer: From function and mechanism to application. Clin Transl Med 2023; 13:e1386. [PMID: 37608500 PMCID: PMC10444973 DOI: 10.1002/ctm2.1386] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 08/10/2023] [Accepted: 08/14/2023] [Indexed: 08/24/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is a malignant tumour, with high morbidity and mortality rates worldwide. The occurrence and development of GC is a complex process involving genetic changes in tumour cells and the influence of the surrounding tumour microenvironment (TME). Accumulative evidence shows that tumour-associated macrophages (TAMs) play a vital role in GC, acting as plentiful and active infiltrating inflammatory cells in the TME. MAIN BODY In this review, the different functions and mechanisms of TAMs in GC progression, including the conversion of phenotypic subtypes; promotion of tumour proliferation, invasion and migration; induction of chemoresistance; promotion of angiogenesis; modulation of immunosuppression; reprogramming of metabolism; and interaction with the microbial community are summarised. Although the role of TAMs in GC remains controversial in clinical settings, clarifying their significance in the treatment selection and prognostic prediction of GC could support optimising TAM-centred clinicaltherapy. CONCLUSION In summary, we reviewed the the phenotypic polarisation, function and molecular mechanism of TAMs and their potential applications in the treatment selection and prognostic prediction of GC.
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Affiliation(s)
- Jie Li
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Juan Sun
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Ziyang Zeng
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Zhen Liu
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Mingwei Ma
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Zicheng Zheng
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Yixuan He
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Weiming Kang
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople's Republic of China
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Cao X, Lai SWT, Chen S, Wang S, Feng M. Targeting tumor-associated macrophages for cancer immunotherapy. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 368:61-108. [PMID: 35636930 DOI: 10.1016/bs.ircmb.2022.02.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Tumor-associated macrophages (TAMs) are one of the most abundant immune components in the tumor microenvironment and play a plethora of roles in regulating tumorigenesis. Therefore, the therapeutic targeting of TAMs has emerged as a new paradigm for immunotherapy of cancer. Herein, the review summarizes the origin, polarization, and function of TAMs in the progression of malignant diseases. The understanding of such knowledge leads to several distinct therapeutic strategies to manipulate TAMs to battle cancer, which include those to reduce TAM abundance, such as depleting TAMs or inhibiting their recruitment and differentiation, and those to harness or boost the anti-tumor activities of TAMs such as blocking phagocytosis checkpoints, inducing antibody-dependent cellular phagocytosis, and reprogramming TAM polarization. In addition, modulation of TAMs may reshape the tumor microenvironment and therefore synergize with other cancer therapeutics. Therefore, the rational combination of TAM-targeting therapeutics with conventional therapies including radiotherapy, chemotherapy, and other immunotherapies is also reviewed. Overall, targeting TAMs presents itself as a promising strategy to add to the growing repertoire of treatment approaches in the fight against cancer, and it is hopeful that these approaches currently being pioneered will serve to vastly improve patient outcomes and quality of life.
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Affiliation(s)
- Xu Cao
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United States.
| | - Seigmund W T Lai
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United States
| | - Siqi Chen
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United States
| | - Sadira Wang
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United States
| | - Mingye Feng
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United States.
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The Role of Indoleamine 2, 3-Dioxygenase 1 in Regulating Tumor Microenvironment. Cancers (Basel) 2022; 14:cancers14112756. [PMID: 35681736 PMCID: PMC9179436 DOI: 10.3390/cancers14112756] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/19/2022] [Accepted: 05/27/2022] [Indexed: 02/05/2023] Open
Abstract
Indoleamine 2, 3-dioxygenase 1 (IDO1) is a rate-limiting enzyme that metabolizes an essential amino acid tryptophan (Trp) into kynurenine (Kyn), and it promotes the occurrence of immunosuppressive effects by regulating the consumption of Trp and the accumulation of Kyn in the tumor microenvironment (TME). Recent studies have shown that the main cellular components of TME interact with each other through this pathway to promote the formation of tumor immunosuppressive microenvironment. Here, we review the role of the immunosuppression mechanisms mediated by the IDO1 pathway in tumor growth. We discuss obstacles encountered in using IDO1 as a new tumor immunotherapy target, as well as the current clinical research progress.
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Svensson MC, Svensson M, Nodin B, Borg D, Hedner C, Hjalmarsson C, Leandersson K, Jirström K. High Infiltration of CD68+/CD163- Macrophages Is an Adverse Prognostic Factor after Neoadjuvant Chemotherapy in Esophageal and Gastric Adenocarcinoma. J Innate Immun 2022; 14:615-628. [PMID: 35504250 PMCID: PMC9801256 DOI: 10.1159/000524434] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 02/19/2022] [Indexed: 01/03/2023] Open
Abstract
Tumor-associated macrophages (TAMs) have emerged as key players in tumor immunology but demonstrate a continuum of functional states being either tumor suppressive or promoting. Moreover, chemotherapeutic agents have been shown to alter the tumor microenvironment. Perioperative chemotherapy is a standard treatment option for resectable esophageal and gastric (EG) adenocarcinoma. The aim of this study was to investigate the influence of neoadjuvant chemotherapy (NAC) on TAMs to improve the prognostication and treatment course for these patients. The study cohort comprised 148 patients, all of whom were diagnosed with resectable EG adenocarcinoma and treated with NAC. Immunohistochemistry was applied to assess the total infiltration and infiltration into tumor nests (TN) of CD68+/CD163-, CD68+/CD163+, and MARCO+ TAMs, on paired biopsies from primary tumors (PT) pre-NAC, and resected PT and lymph node metastases post-NAC. In pre-NAC specimens, high CD68+/CD163+ infiltration into TN was an unfavorable prognostic factor. No association was found between TAM density in PT pre-NAC and histopathological regression. The density of CD68+/CD163+ TAMs was increased in PT post-NAC, while the density of MARCO+ TAMs was decreased. CD68+/CD163- TAM density was not altered. In post-NAC specimens, higher total as well as TN infiltration of CD68+/CD163- TAMs were adverse prognostic factors. In conclusion, these results suggest that NAC may alter certain TAM subsets in EG adenocarcinoma, along with their functional properties and thus their prognostic value.
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Affiliation(s)
- Maria C. Svensson
- Department of Clinical Sciences Lund, Oncology and Therapeutic Pathology, Lund University, Lund, Sweden
| | - Maja Svensson
- Department of Clinical Sciences Lund, Oncology and Therapeutic Pathology, Lund University, Lund, Sweden,*Maria C. Svensson,
| | - Björn Nodin
- Department of Clinical Sciences Lund, Oncology and Therapeutic Pathology, Lund University, Lund, Sweden
| | - David Borg
- 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
| | - Claes Hjalmarsson
- Department of Clinical Sciences Lund, Oncology, Lund University, Lund, Sweden
| | - Karin Leandersson
- Cancer Immunology, Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Karin Jirström
- Department of Clinical Sciences Lund, Oncology and Therapeutic Pathology, Lund University, Lund, Sweden
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10
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Na HY, Park Y, Nam SK, Koh J, Kwak Y, Ahn SH, Park DJ, Kim HH, Lee KS, Lee HS. Prognostic significance of natural killer cell-associated markers in gastric cancer: quantitative analysis using multiplex immunohistochemistry. J Transl Med 2021; 19:529. [PMID: 34952595 PMCID: PMC8710020 DOI: 10.1186/s12967-021-03203-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/16/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Natural killer (NK) cells mediate the anti-tumoral immune response as an important component of innate immunity. The aim of this study was to investigate the prognostic significance and functional implication of NK cell-associated surface receptors in gastric cancer (GC) by using multiplex immunohistochemistry (mIHC). METHODS We performed an mIHC on tissue microarray slides, including 55 GC tissue samples. A total of 11 antibodies including CD57, NKG2A, CD16, HLA-E, CD3, CD20, CD45, CD68, CK, SMA, and ki-67 were used. CD45 + CD3-CD57 + cells were considered as CD57 + NK cells. RESULTS Among CD45 + immune cells, the proportion of CD57 + NK cell was the lowest (3.8%), whereas that of CD57 + and CD57- T cells (65.5%) was the highest, followed by macrophages (25.4%), and B cells (5.3%). CD57 + NK cells constituted 20% of CD45 + CD57 + immune cells while the remaining 80% were CD57 + T cells. The expression of HLA-E in tumor cells correlated with that in tumoral T cells, B cells, and macrophages, but not CD57 + NK cells. The higher density of tumoral CD57 + NK cells and tumoral CD57 + NKG2A + NK cells was associated with inferior survival. CONCLUSIONS Although the number of CD57 + NK cells was lower than that of other immune cells, CD57 + NK cells and CD57 + NKG2A + NK cells were significantly associated with poor outcomes, suggesting that NK cell subsets play a critical role in GC progression. NK cells and their inhibitory receptor, NKG2A, may be potential targets in GC.
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Affiliation(s)
- Hee Young Na
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Yujun Park
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Soo Kyung Nam
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Jiwon Koh
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
- Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Yoonjin Kwak
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
- Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Sang-Hoon Ahn
- Department of Surgery, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
| | - Do Joong Park
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Hyung-Ho Kim
- Department of Surgery, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Kyu Sang Lee
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea.
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
| | - Hye Seung Lee
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
- Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
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11
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Yu X, Yu B, Fang W, Xiong J, Ma M. Identification hub genes of consensus molecular subtype correlation with immune infiltration and predict prognosis in gastric cancer. Discov Oncol 2021; 12:41. [PMID: 35201473 PMCID: PMC8777542 DOI: 10.1007/s12672-021-00434-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/16/2021] [Indexed: 11/19/2022] Open
Abstract
Gastric cancer (GC) has a great fatality rate, meanwhile, there is still a lack of available biomarkers for prognosis. The goal of the research was to discover key and novel potential biomarkers for GC. We screened for the expression of significantly altered genes based on survival rates from two consensus molecular subtypes (CMS) of GC. Subsequently, functional enrichment analysis showed these genes involved in many cancers. And we picked 6 hub genes that could both secreted in the tumor microenvironment and expression enhanced in immune cells. Then, Kaplan Meier survival and expression detected in the tumor pathological stage were utilized to clarify the prognostic of these 6 hub genes. The results indicated that OGN, CHRDL2, C2orf40, THBS4, CHRDL1, and ANGPTL1, respectively, were significantly associated with poor OS in GC patients. And their expression increased with cancer advanced. Moreover, immune infiltration analysis displayed that those hub genes expression positively with M2 macrophage, CD8+ T Cell, most immune inhibitors, and majority immunostimulators. In summary, our results suggested that OGN, CHRDL2, C2orf40, THBS4, CHRDL1, and ANGPTL1 were all potential biomarkers for GC prognosis and might also be potential therapeutic targets for GC.
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Affiliation(s)
- Xin Yu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Bin Yu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Weidan Fang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
| | - Mei Ma
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
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12
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Tang L, Mei Y, Shen Y, He S, Xiao Q, Yin Y, Xu Y, Shao J, Wang W, Cai Z. Nanoparticle-Mediated Targeted Drug Delivery to Remodel Tumor Microenvironment for Cancer Therapy. Int J Nanomedicine 2021; 16:5811-5829. [PMID: 34471353 PMCID: PMC8403563 DOI: 10.2147/ijn.s321416] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/14/2021] [Indexed: 12/24/2022] Open
Abstract
Advanced research has revealed the crucial role of tumor microenvironment (TME) in tumorigenesis. TME consists of a complicated network with a variety of cell types including endothelial cells, pericytes, immune cells, cancer-associated fibroblasts (CAFs), cancer stem cells (CSCs) as well as the extracellular matrix (ECM). The TME-constituting cells interact with the cancerous cells through plenty of signaling mechanisms and pathways in a dynamical way, participating in tumor initiation, progression, metastasis, and response to therapies. Hence, TME is becoming an attractive therapeutic target in cancer treatment, exhibiting potential research interest and clinical benefits. Presently, the novel nanotechnology applied in TME regulation has made huge progress. The nanoparticles (NPs) can be designed as demand to precisely target TME components and to inhibit tumor progression through TME modulation. Moreover, nanotechnology-mediated drug delivery possesses many advantages including prolonged circulation time, enhanced bioavailability and decreased toxicity over traditional therapeutic modality. In this review, update information on TME remodeling through NPs-based targeted drug delivery strategies for anticancer therapy is summarized.
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Affiliation(s)
- Lu Tang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.,NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing, 210009, People's Republic of China
| | - Yijun Mei
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.,NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing, 210009, People's Republic of China
| | - Yan Shen
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.,NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing, 210009, People's Republic of China
| | - Shun He
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.,NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing, 210009, People's Republic of China
| | - Qiaqia Xiao
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.,NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing, 210009, People's Republic of China
| | - Yue Yin
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.,NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing, 210009, People's Republic of China
| | - Yonggang Xu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, People's Republic of China
| | - Jie Shao
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, People's Republic of China
| | - Wei Wang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.,NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing, 210009, People's Republic of China
| | - Zihao Cai
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, People's Republic of China
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13
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Hu J, Ma Y, Ma J, Yang Y, Ning Y, Zhu J, Wang P, Chen G, Liu Y. M2 Macrophage-Based Prognostic Nomogram for Gastric Cancer After Surgical Resection. Front Oncol 2021; 11:690037. [PMID: 34458140 PMCID: PMC8397443 DOI: 10.3389/fonc.2021.690037] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 06/29/2021] [Indexed: 12/24/2022] Open
Abstract
A good prediction model is useful to accurately predict patient prognosis. Tumor-node-metastasis (TNM) staging often cannot accurately predict prognosis when used alone. Some researchers have shown that the infiltration of M2 macrophages in many tumors indicates poor prognosis. This approach has the potential to predict prognosis more accurately when used in combination with TNM staging, but there is less research in gastric cancer. A multivariate analysis demonstrated that CD163 expression, TNM staging, age, and gender were independent risk factors for overall survival. Thus, these parameters were assessed to develop the nomogram in the training data set, which was tested in the validation and whole data sets. The model showed a high degree of discrimination, calibration, and good clinical benefit in the training, validation, and whole data sets. In conclusion, we combined CD163 expression in macrophages, TNM staging, age, and gender to develop a nomogram to predict 3- and 5-year overall survivals after curative resection for gastric cancer. This model has the potential to provide further diagnostic and prognostic value for patients with gastric cancer.
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Affiliation(s)
- Jianwen Hu
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yongchen Ma
- Endoscopy Center, Peking University First Hospital, Beijing, China
| | - Ju Ma
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yanpeng Yang
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yingze Ning
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Jing Zhu
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Pengyuan Wang
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Guowei Chen
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yucun Liu
- Department of General Surgery, Peking University First Hospital, Beijing, China
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14
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Debacker JM, Gondry O, Lahoutte T, Keyaerts M, Huvenne W. The Prognostic Value of CD206 in Solid Malignancies: A Systematic Review and Meta-Analysis. Cancers (Basel) 2021; 13:cancers13143422. [PMID: 34298638 PMCID: PMC8305473 DOI: 10.3390/cancers13143422] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/02/2021] [Accepted: 07/05/2021] [Indexed: 01/03/2023] Open
Abstract
Simple Summary The role of innate immune cells in the tumor microenvironment (TME), more specifically the presence of the tumor associated macrophages (TAMs), is becoming more important in the prognosis and treatment of patients diagnosed with malignancies. The aim of this systematic review and meta-analysis was to assess the potential prognostic value of CD206-expressing TAMs, a subclass of macrophages, which were previously proposed to negatively impact the patient’s prognosis. We identified 27 manuscripts describing the role of CD206 in patient prognosis for 14 different tumor types. Despite a large heterogeneity in the results, we identified a significantly worse overall and disease-free survival for patients with increased CD206-expressing TAMs in the TME. The use of CD206-expressing TAMs could therefore be used as a prognostic marker in patients diagnosed with solid malignancies. Abstract An increased presence of CD206-expressing tumor associated macrophages in solid cancers was proposed to be associated with worse outcomes in multiple types of malignancies, but contradictory results are published. We performed a reproducible systematic review and meta-analysis to provide increased evidence to confirm or reject this hypothesis following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. The Embase, Web of Science, and MEDLINE-databases were systematically searched for eligible manuscripts. A total of 27 papers studying the prognostic impact of CD206 in 14 different tumor types were identified. Meta-analyses showed a significant impact on the overall survival (OS) and disease-free survival (DFS). While no significant differences were revealed in progression-free survival (PFS) and disease-specific survival (DSS), a shift towards negative survival was correlated with increased CD206-expresion. As a result of the different tumor types, large heterogeneity was present between the different tumor types. Subgroup analysis of hepatocellular carcinoma and gastric cancers revealed no heterogeneity, associated with a significant negative impact on OS in both groups. The current systematic review displays the increased presence CD206-expressing macrophages as a significant negative prognostic biomarker for both OS and DFS in patients diagnosed with solid cancers. Because a heterogenous group of tumor types was included in the meta-analysis, the results cannot be generalized. These results can, however, be used to further lead follow-up research to validate the specific prognostic value of CD206 in individual tumor types and therapeutic approaches.
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Affiliation(s)
- Jens M. Debacker
- Department of Head and Skin, Ghent University, 9000 Ghent, Belgium;
- Department of Head and Neck Surgery, Ghent University Hospital, 9000 Ghent, Belgium
- Department of Nuclear Medicine, University Hospital Brussels, 1090 Brussels, Belgium; (O.G.); (T.L.); (M.K.)
- Correspondence: ; Tel.: +32-9-332-39-90
| | - Odrade Gondry
- Department of Nuclear Medicine, University Hospital Brussels, 1090 Brussels, Belgium; (O.G.); (T.L.); (M.K.)
- In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel, 1090 Brussels, Belgium
| | - Tony Lahoutte
- Department of Nuclear Medicine, University Hospital Brussels, 1090 Brussels, Belgium; (O.G.); (T.L.); (M.K.)
- In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel, 1090 Brussels, Belgium
| | - Marleen Keyaerts
- Department of Nuclear Medicine, University Hospital Brussels, 1090 Brussels, Belgium; (O.G.); (T.L.); (M.K.)
- In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel, 1090 Brussels, Belgium
| | - Wouter Huvenne
- Department of Head and Skin, Ghent University, 9000 Ghent, Belgium;
- Department of Head and Neck Surgery, Ghent University Hospital, 9000 Ghent, Belgium
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15
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Zhang H, Zhu G. Beyond Promoter: The Role of Macrophage in Invasion and Progression of Renal Cell Carcinoma. Curr Stem Cell Res Ther 2021; 15:588-596. [PMID: 32096752 DOI: 10.2174/1574888x15666200225093210] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 08/28/2019] [Accepted: 12/11/2019] [Indexed: 11/22/2022]
Abstract
Renal cell carcinoma (RCC) is one of the common urologic neoplasms, and its incidence has been increasing over the past several decades; however, its pathogenesis is still unknown up to now. Recent studies have found that in addition to tumor cells, other cells in the tumor microenvironment also affect the biological behavior of the tumor. Among them, macrophages exist in a large amount in tumor microenvironment, and they are generally considered to play a key role in promoting tumorigenesis. Therefore, we summarized the recent researches on macrophage in the invasiveness and progression of RCC in latest years, and we also introduced and discussed many studies about macrophage in RCC to promote angiogenesis by changing tumor microenvironment and inhibit immune response in order to activate tumor progression. Moreover, macrophage interactes with various cytokines to promote tumor proliferation, invasion and metastasis, and it also promotes tumor stem cell formation and induces drug resistance in the progression of RCC. The highlight of this review is to make a summary of the roles of macrophage in the invasion and progression of RCC; at the same time to raise some potential and possible targets for future RCC therapy.
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Affiliation(s)
- Haibao Zhang
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Guodong Zhu
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
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16
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Díaz Del Arco C, Ortega Medina L, Estrada Muñoz L, García Gómez de Las Heras S, Fernández Aceñero MJ. Is there still a place for conventional histopathology in the age of molecular medicine? Laurén classification, inflammatory infiltration and other current topics in gastric cancer diagnosis and prognosis. Histol Histopathol 2021; 36:587-613. [PMID: 33565601 DOI: 10.14670/hh-18-309] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Gastric cancer (GC) is the fifth most common cancer and the third cause of cancer-related deaths worldwide. In western countries, more than half of GC patients are diagnosed at advanced stages and 5-year survival rates range between 20-30%. The only curative treatment is surgery, and despite recent advances in oncological therapies, GC prognosis is still poor. The main prognostic tool for patient categorization and treatment selection is the TNM classification, but its limitations are being increasingly recognized. Early recurrences may occur in early-stage disease, and patients at the same stage show heterogeneous outcomes. Thus, there is a need to improve GC stratification and to identify new prognostic factors, which may allow us to select drug-susceptible populations, refine patient grouping for clinical trials and discover new therapeutic targets. Molecular classifications have been developed, but they have not been translated to the clinical practice. On the other hand, histological assessment is cheap and widely available, and it is still a mainstay in the era of molecular medicine. Furthermore, histological features are acquiring new roles as reflectors of the genotype-phenotype correlation, and their potential impact on patient management is currently being analyzed. The aim of this literature review is to provide a modern overview of the histological assessment of GC. In this study, we discuss recent topics on the histological diagnosis of GC, focusing on the current role of Laurén classification and the potential value of new histological features in GC, such as inflammatory infiltration and tumor budding.
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Affiliation(s)
- Cristina Díaz Del Arco
- Department of Surgical Pathology, Hospital Clínico San Carlos, Madrid, Spain.
- Complutense University of Madrid, Madrid, Spain
| | - Luis Ortega Medina
- Complutense University of Madrid, Madrid, Spain
- Department of Surgical Pathology, Hospital Clínico San Carlos, Madrid, Spain
| | | | | | - Mª Jesús Fernández Aceñero
- Complutense University of Madrid, Madrid, Spain
- Department of Surgical Pathology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
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17
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Wang Y, Wang J, Yang C, Wang Y, Liu J, Shi Z, Chen Y, Feng Y, Ma X, Qiao S. A study of the correlation between M2 macrophages and lymph node metastasis of colorectal carcinoma. World J Surg Oncol 2021; 19:91. [PMID: 33781288 PMCID: PMC8008636 DOI: 10.1186/s12957-021-02195-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Accepted: 03/15/2021] [Indexed: 12/24/2022] Open
Abstract
Background Lymph node metastasis is a major prognostic sign of colorectal carcinoma and an important indicator for individualized treatment. M2 macrophages play a key role in carcinogenesis and tumor development by enhancing invasiveness and promoting lymph node metastasis. The purpose of this study was to investigate the effect of CD163-positive M2 macrophages on lymph node metastasis in colorectal carcinoma. Methods Postoperative lymph node tissues were obtained from 120 patients with colorectal carcinoma who underwent radical surgery in the First Affiliated Hospital of Jinzhou Medical University between December 2019 and May 2020. We detected the expression of the CD163 protein in lymph nodes using immunohistochemistry. Furthermore, the relationships between M2 macrophages identified by expression of CD163 and lymph node metastasis were analyzed using the independent sample t-test and Chi-square test. Results M2 macrophages were increased in metastatic lymph nodes and non-metastatic lymph nodes adjacent to the cancer. The M2 macrophage count was higher in patients with macro-metastases than in patients with micro-metastases. Conclusions The presence of M2 macrophages represents an important indicator for lymph node metastasis in colorectal carcinoma and may be a potential marker for its prediction. Thus, M2 macrophage localization might offer a new target for the comprehensive treatment of colorectal carcinoma.
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Affiliation(s)
- Yanping Wang
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, No. 2, The Fifth Section of Renmin Street, Guta, Jinzhou, 121000, Liaoning, People's Republic of China
| | - Jikun Wang
- Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, Liaoning, People's Republic of China
| | - Chunyu Yang
- Department of Pathology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, Liaoning, People's Republic of China
| | - Yue Wang
- Department of Pathology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, Liaoning, People's Republic of China
| | - Jinhao Liu
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, No. 2, The Fifth Section of Renmin Street, Guta, Jinzhou, 121000, Liaoning, People's Republic of China
| | - Zuoxiu Shi
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, No. 2, The Fifth Section of Renmin Street, Guta, Jinzhou, 121000, Liaoning, People's Republic of China
| | - Yanlei Chen
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, No. 2, The Fifth Section of Renmin Street, Guta, Jinzhou, 121000, Liaoning, People's Republic of China
| | - Yang Feng
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, No. 2, The Fifth Section of Renmin Street, Guta, Jinzhou, 121000, Liaoning, People's Republic of China
| | - Xueqian Ma
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, No. 2, The Fifth Section of Renmin Street, Guta, Jinzhou, 121000, Liaoning, People's Republic of China
| | - Shifeng Qiao
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, No. 2, The Fifth Section of Renmin Street, Guta, Jinzhou, 121000, Liaoning, People's Republic of China.
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18
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Prognostic significance and targeting tumor-associated macrophages in cancer: new insights and future perspectives. Breast Cancer 2021; 28:539-555. [PMID: 33661479 DOI: 10.1007/s12282-021-01231-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 02/18/2021] [Indexed: 02/06/2023]
Abstract
Macrophages are phagocytic sentinel cells of the immune system that are central to both innate and adaptive immune responses and serve as the first line of defense against pathogenic insults to tissues. In the tumor microenvironment, tumor-derived factors induce monocyte polarization towards a pro-tumor phenotype. The pro-tumor macrophages regulate key steps in tumorigenicity including tumor growth, angiogenesis, immune suppression, and metastasis. Macrophage infiltration in solid tumors correlates with poor prognosis and resistance to chemotherapy in most cancers. Here in this review, we will shed light on tumor-associated macrophages (TAMs) in regulating tumorigenicity and TAMs as a prognostic biomarker. Also, we will review the recent advances in targeting TAMs to increase the prognosis of cancer patients.
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19
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An Overview of Advances in Cell-Based Cancer Immunotherapies Based on the Multiple Immune-Cancer Cell Interactions. Methods Mol Biol 2021; 2097:139-171. [PMID: 31776925 DOI: 10.1007/978-1-0716-0203-4_10] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Tumors have a complex ecosystem in which behavior and fate are determined by the interaction of diverse cancerous and noncancerous cells at local and systemic levels. A number of studies indicate that various immune cells participate in tumor development (Fig. 1). In this review, we will discuss interactions among T lymphocytes (T cells), B cells, natural killer (NK) cells, dendritic cells (DCs), tumor-associated macrophages (TAMs), neutrophils, and myeloid-derived suppressor cells (MDSCs). In addition, we will touch upon attempts to either use or block subsets of immune cells to target cancer.
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20
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Guo M, Li W, Li B, Zou B, Wang S, Fan B, Sun X, Wang L. Multiple Immune Features-Based Signature for Predicting Recurrence and Survival of Inoperable LA-NSCLC Patients. Front Oncol 2020; 10:571380. [PMID: 33154945 PMCID: PMC7591766 DOI: 10.3389/fonc.2020.571380] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 09/21/2020] [Indexed: 12/28/2022] Open
Abstract
Introduction The immune status of the tumor microenvironment is extremely complex. One single immune feature cannot reflect the integral immune status, and its prognostic value was limited. We postulated that the immune signature based on multiple immuno-features could markedly improve the prediction of post-chemoradiotherapeutic survival in inoperable locally advanced non-small-cell lung cancer (LA-NSCLC) patients. Methods In this study, 100 patients who were diagnosed as having inoperable LA-NSCLC between January 2005 and January 2016 were analyzed. A five immune features-based signature was then constructed using the nested repeat 10-fold cross validation with least absolute shrinkage and selection operator (LASSO) Cox regression model. Nomograms were then established for predicting prognosis. Results The immune signature combining five immuno-features was significantly associated with overall survival (OS) and progression-free survival (PFS) (P = 0.002 and P = 0.014, respectively) in patients with inoperable LA-NSCLC, and at a cutoff of −0.05 stratified patients into two groups with 5-year OS rates of 39.8 and 8.8%, and 2-year PFS rates of 22.2 and 5.5% for the high- and low-immune signature groups, respectively. Integrating immune signature, we proposed predictive nomograms that were better than the traditional TNM staging system in terms of discriminating ability (OS: 0.692 vs. 0.588; PFS: 0.672 vs. 0.586, respectively) or net weight classification (OS: 32.96%; PFS: 9.22%), suggesting that the immune signature plays a significant role in improving the prognostic value. Conclusion Multiple immune features-based immune signature could effectively predict recurrence and survival of inoperable LA-NSCLC patients and complemented the prognostic value of the TNM staging system.
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Affiliation(s)
- Meiying Guo
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, China
| | - Wanlong Li
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Butuo Li
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.,Key Laboratory of Cancer Prevention and Therapy, Department of Radiation Oncology, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Bing Zou
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Shijiang Wang
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Bingjie Fan
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Xindong Sun
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Linlin Wang
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
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21
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Nasr R, Shamseddine A, Mukherji D, Nassar F, Temraz S. The Crosstalk between Microbiome and Immune Response in Gastric Cancer. Int J Mol Sci 2020; 21:ijms21186586. [PMID: 32916853 PMCID: PMC7556019 DOI: 10.3390/ijms21186586] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 08/04/2020] [Accepted: 08/12/2020] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is the end result of a complex interplay between host genetics, environmental factors, and microbial factors. The link between gut microbiome and gastric cancer has been attributed to persistent activation of the host's immune system by gut microbiota. The end result of this dysregulated interaction between host epithelium and microbes is a state of chronic inflammation. Gut bacteria can promote anti-tumor immune responses through several mechanisms. These include triggering T-cell responses to bacterial antigens that can cross-react with tumor antigens or cause tumor-specific antigen recognition; engagement of pattern recognition receptors that mediate pro-immune or anti-inflammatory effects or via small metabolites that mediate systemic effects on the host. Here we review the role of the gut microbiome including H. pylori and non-H. pylori gastric bacteria, the immune response, and immunotherapy using checkpoint inhibitors. We also review the evidence for cross talk between the gut microbiome and immune response in gastric cancer.
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Affiliation(s)
- Rihab Nasr
- Department of Anatomy, Cell Biology and Physiology, American University of Beirut Medical Center, Riad El Solh, Beirut 1107, Lebanon;
| | - Ali Shamseddine
- Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, Beirut 1107, Lebanon; (A.S.); (D.M.); (F.N.)
| | - Deborah Mukherji
- Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, Beirut 1107, Lebanon; (A.S.); (D.M.); (F.N.)
| | - Farah Nassar
- Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, Beirut 1107, Lebanon; (A.S.); (D.M.); (F.N.)
| | - Sally Temraz
- Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, Beirut 1107, Lebanon; (A.S.); (D.M.); (F.N.)
- Correspondence: ; Tel.: +961-137-4374
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22
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Petty AJ, Li A, Wang X, Dai R, Heyman B, Hsu D, Huang X, Yang Y. Hedgehog signaling promotes tumor-associated macrophage polarization to suppress intratumoral CD8+ T cell recruitment. J Clin Invest 2020; 129:5151-5162. [PMID: 31638600 DOI: 10.1172/jci128644] [Citation(s) in RCA: 204] [Impact Index Per Article: 40.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 08/20/2019] [Indexed: 12/21/2022] Open
Abstract
Tumor-associated macrophages (TAMs) usually display an antiinflammatory M2-like phenotype to facilitate tumor growth. However, what drives M2 polarization of TAMs and how TAMs suppress antitumor immunity within the tumor microenvironment (TME) remain largely undefined. Using several murine tumor models, we showed that hedgehog (Hh) signaling in myeloid cells is critical for TAM M2 polarization and tumor growth. We also found that tumor cells secrete sonic hedgehog (SHH), an Hh ligand, and that tumor-derived SHH drives TAM M2 polarization. Furthermore, Hh-induced functional polarization in TAMs suppresses CD8+ T cell recruitment to the TME through the inhibition of CXCL9 and CXCL10 production by TAMs. Last, we demonstrated that Krüppel-like factor 4 (Klf4) mediates Hh-dependent TAM M2 polarization and the immunosuppressive function. Collectively, these findings highlight a critical role for tumor-derived SHH in promoting TAM M2 polarization, a mechanism for TAM-mediated immunosuppression, and may provide insights into the design of new cancer immunotherapeutic strategies.
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Affiliation(s)
- Amy J Petty
- Department of Pharmacology and Cancer Biology.,Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, and
| | - Ang Li
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, and
| | - Xinyi Wang
- Department of Pharmacology and Cancer Biology.,Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, and
| | - Rui Dai
- Department of Pharmacology and Cancer Biology.,Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, and
| | - Benjamin Heyman
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, and
| | - David Hsu
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, and
| | - Xiaopei Huang
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, and
| | - Yiping Yang
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, and.,Department of Immunology, Duke University, Durham, North Carolina, USA
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23
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Blessin NC, Spriestersbach P, Li W, Mandelkow T, Dum D, Simon R, Hube-Magg C, Lutz F, Viehweger F, Lennartz M, Fraune C, Nickelsen V, Fehrle W, Göbel C, Weidemann S, Clauditz T, Lebok P, Möller K, Steurer S, Izbicki JR, Sauter G, Minner S, Jacobsen F, Luebke AM, Büscheck F, Höflmayer D, Wilczak W, Burandt E, Hinsch A. Prevalence of CD8 + cytotoxic lymphocytes in human neoplasms. Cell Oncol (Dordr) 2020; 43:421-430. [PMID: 32141029 PMCID: PMC7214387 DOI: 10.1007/s13402-020-00496-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/07/2020] [Indexed: 12/17/2022] Open
Abstract
PURPOSE Immune checkpoint inhibitors have recently been approved by the US FDA as first and/or second line therapy in a subset of cancer types. Recent evidence suggests that the quantity of tumor infiltrating lymphocytes (TILs) influences the likelihood of response to immune checkpoint inhibitors. Here, we set out to assess the density of CD8+ lymphocytes in a wide range of different cancer types and subtypes. METHODS The density of CD8+ lymphocytes was compared across different cancer types using tissue microarrays (TMAs) composed of up to 50 tumor samples each from 84 different cancer types and subtypes. In total 2652 cancers and 608 normal tissues were successfully analyzed by CD8 immunohistochemistry followed by automated image analysis of digitized slides. RESULTS We found that the median CD8+ lymphocyte counts ranged from 6 cells/mm2 in pleomorphic adenoma up to 1573 cells/mm2 in Hodgkin's lymphoma. The CD8 counts were generally lower in normal tissues compared to cancer tissues. Blood vessels of the spleen were the only non-lymphatic tissue staining positive for CD8. Tumor types approved for checkpoint inhibitor therapy, including malignant melanoma (81), muscle invasive urothelial carcinoma (119), small cell lung cancer (120), clear cell renal cell cancer (153), squamous cell carcinoma (189) and adenocarcinoma of the lung (328) as well as Hodgkin's lymphoma (1573) were all ranking among the upper half of our list. Comparably high CD8 densities (median cells/mm2) were also found in several rare and aggressive cancer types including Merkel cell carcinoma (70), angiosarcoma (95), anaplastic thyroid cancer (156) and embryonal carcinoma of the testis (186). In 73 of the 84 analyzed cancer types, the highly variable CD8 counts occasionally exceeded the average CD8 count of tumors for which checkpoint inhibitors have been approved. CONCLUSION These data support the concept that among most tumor types at least some individual cancers may benefit from treatment with immune checkpoint inhibitors.
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Affiliation(s)
- Niclas C Blessin
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Patrick Spriestersbach
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Wenchao Li
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Tim Mandelkow
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - David Dum
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany.
| | - Claudia Hube-Magg
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Florian Lutz
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Florian Viehweger
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Maximillian Lennartz
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Christoph Fraune
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Vera Nickelsen
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Wilfried Fehrle
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Cosima Göbel
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Sören Weidemann
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Till Clauditz
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Patrick Lebok
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Katharina Möller
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Stefan Steurer
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Jacob R Izbicki
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Guido Sauter
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Sarah Minner
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Frank Jacobsen
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Andreas M Luebke
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Franziska Büscheck
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Doris Höflmayer
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Waldemar Wilczak
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Eike Burandt
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Andrea Hinsch
- Institute of Pathology, Martinistraße 52, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
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24
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Tumor-associated macrophage-derived exosomal microRNA-155-5p stimulates intracranial aneurysm formation and macrophage infiltration. Clin Sci (Lond) 2020; 133:2265-2282. [PMID: 31657855 DOI: 10.1042/cs20190680] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 10/17/2019] [Accepted: 10/28/2019] [Indexed: 12/22/2022]
Abstract
Tumor-associated macrophages (TAMs) play a regulatory role in inflammation and cancer. Exosomes derived from macrophages carrying microRNAs (miRNAs or miRs) are of great value for cancer therapy. Gremlin 1 (GREM1), a member of the antagonists of secreted bone morphogenetic protein, has been implicated in the pathophysiology of multiple diseases or cancers. Based on the predictions of miRNA-mRNA interaction, GREM1 was found to be a target gene of miR-155-5p. Here, the present study aims to explore the role of TAM-derived exosomal miR-155-5p by regulating GREM1 in intracranial aneurysm (IA). The collected results showed that GREM1 was down-regulated in IA, while miR-155-5p was up-regulated in TAM-derived exosomes. Smooth muscle cells (SMCs) were co-cultured with TAMs or exposed to exosomes derived from TAMs transfected with either miR-155-5p mimic or miR-155-5p inhibitor for exploring their roles in proliferation and migration of SMCs in vitro. Accordingly, in vitro experiments showed that TAM-derived exosomal miR-155-5p could promote proliferation and migration of SMCs by targeting GREM1. The effects of TAM-derived exosomal miR-155-5p on IA formation and TAM activation and infiltration by regulation of GREM1 in vivo were measured in IA rats injected with exosomes or those from TAMs transfected with miR-155-5p inhibitor. In vivo experimental results consistently confirmed that TAM-derived exosomes carrying miR-155-5p promoted IA formation and TAM activation and infiltration. In conclusion, TAM-derived exosomal miR-155-5p promotes IA formation via GREM1, which points to miR-155-5p as a possible therapeutic target for IA.
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25
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Neuropilin1 Expression Acts as a Prognostic Marker in Stomach Adenocarcinoma by Predicting the Infiltration of Treg Cells and M2 Macrophages. J Clin Med 2020; 9:jcm9051430. [PMID: 32408477 PMCID: PMC7290937 DOI: 10.3390/jcm9051430] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 04/27/2020] [Accepted: 05/09/2020] [Indexed: 12/14/2022] Open
Abstract
Neuropilin1 (NRP1) plays a critical role in tumor progression and immune responses. Although the roles of NRP1 in various tumors have been investigated, the clinical relevance of NRP1 expression in stomach adenocarcinoma (STAD) has not been studied. To investigate the use of NRP1 as a prognostic biomarker of STAD, we analyzed NRP1 mRNA expression and its correlation with patient survival and immune cell infiltration using various databases. NRP1 mRNA expression was significantly higher in STAD than normal tissues, and Kaplan-Meier survival analysis showed that NRP1 expression was significantly associated with poor prognosis in patients with STAD. To elucidate the related mechanism, we analyzed the correlation between NRP1 expression and immune cell infiltration level. In particular, the infiltration of immune-suppressive cells, such as regulatory T (Treg) cells and M2 macrophage, was significantly increased by NRP1 expression. In addition, the expression of interleukin (IL)-35, IL-10, and TGF-β1 was also positively correlated with NRP1 expression, resulting in the immune suppression. Collectively in this study, our integrated analysis using various clinical databases shows that the significant correlation between NRP1 expression and the infiltration of Treg cells and M2 macrophage explains poor prognosis mechanism in STAD, suggesting the clinical relevance of NRP1 expression as a prognostic biomarker for STAD patients.
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26
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Yan Y, Zhang R, Zhang Y, Zhang X, Zhang A, Bu X. Recombinant Newcastle disease virus expressing human IFN-λ1 (rL-hIFN-λ1) inhibits lung cancer migration through repolarizating macrophage from M2 to M1 phenotype. Transl Cancer Res 2020; 9:3392-3405. [PMID: 35117705 PMCID: PMC8798182 DOI: 10.21037/tcr-19-2320] [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] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 02/05/2020] [Indexed: 12/04/2022]
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) are frequently infiltrated in tumor microenvironment and promote tumor progression. Lung cancer development largely depends upon the essential contributions from the TAMs which generally polarize into M2 TAMs and produce abundant anti-inflammatory factors and facilitate tumor development. The recombinant Newcastle disease virus expressing human IFN-λ1 (rL-hIFN-λ1) could regulate Th1/Th2 immune response to produce anti-tumor microenvironment. However, the interaction between rL-hIFN-λ1 and macrophages polarization remains unclear. METHODS The THP-1 cells were used to construct the THP-1-M0, THP-1-M1, THP-1-M2 and THP-1-rL-hIFN-λ1 macrophage models. qRT-PCR and Immunofluorescence were used to detect the polarization phenotype of macrophage polarized by rL-hIFN-λ1. The inhibitory properties of THP-rL-hIFN-λ1 on A549 cells and H446 cells were determined by a Clonogenic assay, as well as scratch migration assays and Transwell were used to explore the capability of migration. Furthermore, the M1/M2 infiltration density in different clinical stages of lung cancer tissues were examined. RESULTS It was showed that rL-hIFN-λ1 could induce normal macrophages to differentiate into THP-1-M1 macrophages. Meanwhile, rL-hIFN-λ1 could also direct THP-1-M2 macrophages polarization into THP-1-M1 macrophages. Supernatants from rL-hIFN-λl induced macrophages inhibited colony formation, migration and invasion of lung cancer cells in vitro which was similar to THP-1-M1 macrophages. Moreover, analysis of clinical tumor tissues indicated that M1-type macrophages decreased gradually with the development of the clinical stage of lung cancer. CONCLUSIONS Therefore, rL-hIFN-λl induced significant suppression of primary lung tumor growth and spontaneous lung metastases through regulating macrophages function, and it was expected to become a new biological therapy for lung cancer.
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Affiliation(s)
- Yulan Yan
- Department of Respiratory Medicine, Affiliated People’s Hospital of Jiangsu University, Zhenjiang 212002, China
| | - Riting Zhang
- Department of Respiratory Medicine, Affiliated People’s Hospital of Jiangsu University, Zhenjiang 212002, China
- Clinical Medicine College of Jiangsu University, Zhenjiang 212013, China
| | - Yao Zhang
- Clinical Medicine College of Jiangsu University, Zhenjiang 212013, China
| | - Xuanfeng Zhang
- Clinical Medicine College of Jiangsu University, Zhenjiang 212013, China
| | - Anwei Zhang
- Clinical Medicine College of Jiangsu University, Zhenjiang 212013, China
| | - Xuefeng Bu
- Department of General Surgery, Affiliated People’s Hospital of Jiangsu University, Zhenjiang 212002, China
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27
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Kim Y, Rhee YY, Wen X, Cho NY, Bae JM, Kim WH, Kang GH. Combination of L1 methylation and tumor-infiltrating lymphocytes as prognostic marker in advanced gastric cancer. Gastric Cancer 2020; 23:464-472. [PMID: 31691036 DOI: 10.1007/s10120-019-01025-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Accepted: 10/18/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND High density of tumor-infiltrating lymphocyte (TIL) is known to be associated with prolonged survival time, whereas tumoral-L1 hypomethylation has been associated with shortened survival time in patients with gastric cancer (GC). Since L1-methylation level is high in lymphocytes, higher density of TIL could lead to higher measurement of L1-methylation level in cancer tissues which contain cancer cells as well as non-neoplastic cells, including TIL. Putative interaction of TIL in the relationship between L1-methylation level and survival led us to explore combinatory statuses of tumoral-L1-methylation level and TIL density as a prognostic marker in GC. METHODS TIL and tumoral-L1-methylation level were measured in advanced GC samples (n = 491), using CD3 immunohistochemistry and pyrosequencing-methylation analysis, respectively. TIL density was measured in tumor center and invasive front areas. RESULTS TIL density correlated with tumoral-L1-methylation level but the relationship was weak. Combinatory statuses of L1-methylation level and CD3 TIL density were found to be statistically significant in survival analysis. Multivariate analysis revealed that the relationship between combinatory statuses and survival was independent. Prognostic value of the combinatory statuses at invasive front was significant in an independent set. CONCLUSIONS Our findings indicate that tumoral-L1-methylation level is correlated with TIL density and that combinatory statuses might help to find a subset of GCs with worse clinical outcome in GCs with low-L1-methylation status or a subset of GCs with better clinical outcome in GCs with high-L1-methylation status.
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Affiliation(s)
- Younghoon Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Ye-Young Rhee
- Pathology Center, Seegene Medical Foundation, Seoul, Korea
| | - Xianyu Wen
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Nam-Yun Cho
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong Mo Bae
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Woo Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Gyeong Hoon Kang
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea. .,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
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28
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Quintana E, Schulze CJ, Myers DR, Choy TJ, Mordec K, Wildes D, Shifrin NT, Belwafa A, Koltun ES, Gill AL, Singh M, Kelsey S, Goldsmith MA, Nichols R, Smith JAM. Allosteric Inhibition of SHP2 Stimulates Antitumor Immunity by Transforming the Immunosuppressive Environment. Cancer Res 2020; 80:2889-2902. [PMID: 32350067 DOI: 10.1158/0008-5472.can-19-3038] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 02/23/2020] [Accepted: 04/22/2020] [Indexed: 11/16/2022]
Abstract
The protein tyrosine phosphatase SHP2 binds to phosphorylated signaling motifs on regulatory immunoreceptors including PD-1, but its functional role in tumor immunity is unclear. Using preclinical models, we show that RMC-4550, an allosteric inhibitor of SHP2, induces antitumor immunity, with effects equivalent to or greater than those resulting from checkpoint blockade. In the tumor microenvironment, inhibition of SHP2 modulated T-cell infiltrates similar to checkpoint blockade. In addition, RMC-4550 drove direct, selective depletion of protumorigenic M2 macrophages via attenuation of CSF1 receptor signaling and increased M1 macrophages via a mechanism independent of CD8+ T cells or IFNγ. These dramatic shifts in polarized macrophage populations in favor of antitumor immunity were not seen with checkpoint blockade. Consistent with a pleiotropic mechanism of action, RMC-4550 in combination with either checkpoint or CSF1R blockade caused additive antitumor activity with complete tumor regressions in some mice; tumors intrinsically sensitive to SHP2 inhibition or checkpoint blockade were particularly susceptible. Our preclinical findings demonstrate that SHP2 thus plays a multifaceted role in inducing immune suppression in the tumor microenvironment, through both targeted inhibition of RAS pathway-dependent tumor growth and liberation of antitumor immune responses. Furthermore, these data suggest that inhibition of SHP2 is a promising investigational therapeutic approach. SIGNIFICANCE: Inhibition of SHP2 causes direct and selective depletion of protumorigenic M2 macrophages and promotes antitumor immunity, highlighting an investigational therapeutic approach for some RAS pathway-driven cancers.
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Affiliation(s)
- Elsa Quintana
- Department of Biology, Revolution Medicines, Inc., Redwood City, California
| | | | - Darienne R Myers
- Department of Biology, Revolution Medicines, Inc., Redwood City, California
| | - Tiffany J Choy
- Department of Biology, Revolution Medicines, Inc., Redwood City, California
| | - Kasia Mordec
- Department of Biology, Revolution Medicines, Inc., Redwood City, California
| | - David Wildes
- Department of Biology, Revolution Medicines, Inc., Redwood City, California
| | | | - Amira Belwafa
- Department of Biology, Revolution Medicines, Inc., Redwood City, California
| | - Elena S Koltun
- Department of Chemistry, Revolution Medicines, Inc., Redwood City, California
| | - Adrian L Gill
- Department of Chemistry, Revolution Medicines, Inc., Redwood City, California
| | - Mallika Singh
- Department of Biology, Revolution Medicines, Inc., Redwood City, California
| | - Stephen Kelsey
- Department of Biology, Revolution Medicines, Inc., Redwood City, California.,Department of Chemistry, Revolution Medicines, Inc., Redwood City, California
| | - Mark A Goldsmith
- Department of Biology, Revolution Medicines, Inc., Redwood City, California.,Department of Chemistry, Revolution Medicines, Inc., Redwood City, California
| | - Robert Nichols
- Department of Biology, Revolution Medicines, Inc., Redwood City, California
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29
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The Gastrointestinal Tumor Microenvironment: An Updated Biological and Clinical Perspective. JOURNAL OF ONCOLOGY 2019; 2019:6240505. [PMID: 31885581 PMCID: PMC6893275 DOI: 10.1155/2019/6240505] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 10/30/2019] [Indexed: 12/24/2022]
Abstract
Gastrointestinal cancers are still responsible for high numbers of cancer-related deaths despite advances in therapy. Tumor-associated cells play a key role in tumor biology, by supporting or halting tumor development through the production of extracellular matrix, growth factors, cytokines, and extracellular vesicles. Here, we review the roles of these tumor-associated cells in the initiation, angiogenesis, immune modulation, and resistance to therapy of gastrointestinal cancers. We also discuss novel diagnostic and therapeutic strategies directed at tumor-associated cells and their potential benefits for the survival of these patients.
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Nearchou IP, Lillard K, Gavriel CG, Ueno H, Harrison DJ, Caie PD. Automated Analysis of Lymphocytic Infiltration, Tumor Budding, and Their Spatial Relationship Improves Prognostic Accuracy in Colorectal Cancer. Cancer Immunol Res 2019; 7:609-620. [PMID: 30846441 DOI: 10.1158/2326-6066.cir-18-0377] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 11/15/2018] [Accepted: 01/24/2019] [Indexed: 11/16/2022]
Abstract
Both immune profiling and tumor budding significantly correlate with colorectal cancer patient outcome but are traditionally reported independently. This study evaluated the association and interaction between lymphocytic infiltration and tumor budding, coregistered on a single slide, in order to determine a more precise prognostic algorithm for patients with stage II colorectal cancer. Multiplexed immunofluorescence and automated image analysis were used for the quantification of CD3+CD8+ T cells, and tumor buds (TBs), across whole slide images of three independent cohorts (training cohort: n = 114, validation cohort 1: n = 56, validation cohort 2: n = 62). Machine learning algorithms were used for feature selection and prognostic risk model development. High numbers of TBs [HR = 5.899; 95% confidence interval (CI) 1.875-18.55], low CD3+ T-cell density (HR = 9.964; 95% CI, 3.156-31.46), and low mean number of CD3+CD8+ T cells within 50 μm of TBs (HR = 8.907; 95% CI, 2.834-28.0) were associated with reduced disease-specific survival. A prognostic signature, derived from integrating TBs, lymphocyte infiltration, and their spatial relationship, reported a more significant cohort stratification (HR = 18.75; 95% CI, 6.46-54.43), than TBs, Immunoscore, or pT stage. This was confirmed in two independent validation cohorts (HR = 12.27; 95% CI, 3.524-42.73; HR = 15.61; 95% CI, 4.692-51.91). The investigation of the spatial relationship between lymphocytes and TBs within the tumor microenvironment improves accuracy of prognosis of patients with stage II colorectal cancer through an automated image analysis and machine learning workflow.
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Affiliation(s)
- Ines P Nearchou
- Quantitative and Digital Pathology, School of Medicine, University of St. Andrews, St. Andrews, UK.
| | | | - Christos G Gavriel
- Quantitative and Digital Pathology, School of Medicine, University of St. Andrews, St. Andrews, UK
| | - Hideki Ueno
- Department of Surgery, National Defense Medical College, Saitama, Japan
| | - David J Harrison
- Quantitative and Digital Pathology, School of Medicine, University of St. Andrews, St. Andrews, UK
| | - Peter D Caie
- Quantitative and Digital Pathology, School of Medicine, University of St. Andrews, St. Andrews, UK
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Rakaee M, Busund LTR, Jamaly S, Paulsen EE, Richardsen E, Andersen S, Al-Saad S, Bremnes RM, Donnem T, Kilvaer TK. Prognostic Value of Macrophage Phenotypes in Resectable Non-Small Cell Lung Cancer Assessed by Multiplex Immunohistochemistry. Neoplasia 2019; 21:282-293. [PMID: 30743162 PMCID: PMC6369140 DOI: 10.1016/j.neo.2019.01.005] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 01/14/2019] [Accepted: 01/17/2019] [Indexed: 12/14/2022] Open
Abstract
Macrophages are important inflammatory cells that regulate innate and adaptive immunity in cancer. Tumor-associated macrophages (TAMs) are thought to differentiate into two main phenotypes: proinflammatory M1 and protumorigenic M2. Currently, the prognostic impact of TAMs and their M1 and M2 phenotypes is unclear in non–small cell cancer (NSCLC). The present study was set up to evaluate an approach for identifying common M1 and M2 macrophage markers and explore their clinical significance in NSCLC. Using multiplex chromogenic immunohistochemistry, tissue microarrays of 553 primary tumors and 143 paired metastatic lymph nodes of NSCLC specimens were stained to detect various putative macrophage phenotypes: M1 (HLA-DR/CD68), M2 (CD163/CD68), M2 (CD204/CD68), and pan-macrophage (CD68/CK). Correlation analyses were performed to examine the relationship between TAMs and adaptive/innate immune infiltrates. HLA-DR+/CD68+M1 TAM level significantly decreased from pathological stage I to III. In a compartment-specific correlation analysis, moderate to strong correlations were observed between both TAM subsets (M1 and M2) with CD3-, CD8-, CD4-, and CD45RO-positive immune cells. Survival analyses, in both stromal and intratumoral compartments, revealed that high levels of HLA-DR+/CD68+M1 (stroma, hazard ratio [HR] = 0.73, P = .03; intratumor, HR = 0.7, P = .04), CD204+M2 (stroma, HR = 0.7, P = .02; intratumor, HR = 0.6, P = .004), and CD68 (stroma, HR = 0.69, P = .02; intratumor, HR = 0.73, P = .04) infiltration were independently associated with improved NSCLC-specific survival. In lymph nodes, the intratumoral level of HLA-DR+/CD68+M1 was an independent positive prognostic indicator (Cox model, HR = 0.38, P = .001). In conclusion, high levels of M1, CD204+M2, and CD68 macrophages are independent prognosticators of prolonged survival in NSCLC.
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Affiliation(s)
- Mehrdad Rakaee
- Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, Norway, 9019.
| | - Lill-Tove Rasmussen Busund
- Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, Norway, 9019; Department of Clinical Pathology, University Hospital of North Norway, Tromsø, Norway, 9019.
| | - Simin Jamaly
- Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway, 9019.
| | - Erna-Elise Paulsen
- Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway, 9019; Department of Oncology, University Hospital of North Norway, Tromsø, Norway, 9019.
| | - Elin Richardsen
- Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, Norway, 9019; Department of Clinical Pathology, University Hospital of North Norway, Tromsø, Norway, 9019.
| | - Sigve Andersen
- Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway, 9019; Department of Oncology, University Hospital of North Norway, Tromsø, Norway, 9019.
| | - Samer Al-Saad
- Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, Norway, 9019; Department of Clinical Pathology, University Hospital of North Norway, Tromsø, Norway, 9019.
| | - Roy M Bremnes
- Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway, 9019; Department of Oncology, University Hospital of North Norway, Tromsø, Norway, 9019.
| | - Tom Donnem
- Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway, 9019; Department of Oncology, University Hospital of North Norway, Tromsø, Norway, 9019.
| | - Thomas K Kilvaer
- Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway, 9019; Department of Oncology, University Hospital of North Norway, Tromsø, Norway, 9019.
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Preliminary analysis of single-nucleotide polymorphisms in IL-10, IL-4, and IL-4Rα genes and profile of circulating cytokines in patients with gastric Cancer. BMC Gastroenterol 2018; 18:184. [PMID: 30526523 PMCID: PMC6288868 DOI: 10.1186/s12876-018-0913-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 11/27/2018] [Indexed: 12/14/2022] Open
Abstract
Background Gastric Cancer is highly prevalent and deadly worldwide. In Colombia, it is the most lethal form of cancer. Some single-nucleotide polymorphisms in IL-10, IL-4, and IL-4Rα genes have been associated with an anti-inflammatory environment and a Th2 profile in detriment of the antitumor Th1 response. This research sought to detect single-nucleotide polymorphisms in promoter sequences, like − 1082 (G/A), − 592 (C/A), and − 819 (C/T), as well as − 590 (C/T) of the IL-10 and IL-4 genes, respectively; in addition to the IL-4Rα mutation variants, Ile50Val and Q576R, together with circulating levels of IL-4, TNF-α, IL-10, and IFN-γ in patients with gastric carcinoma in Cúcuta, Colombia. Methods In a cross-sectional study, 17 patients and 30 healthy individuals were genotyped for the six polymorphisms mentioned through PCR-RFLP of DNA obtained from peripheral blood cells and serum samples were analyzed by sandwich ELISA to quantify cytokines. Statistical difference between groups was determined along with the association between the presence of polymorphisms and the risk of gastric cancer, as well as the mortality in patients, using Mann-Whitney U test and logistic regression analysis, respectively. Results An association between the − 1082 (G/A) and the risk of gastric cancer was found (OR = 7.58, range 0.77–74.06, P = 0.08). Furthermore, patients had a significant increase in IL-4 serum levels (P < 0.01) compared to healthy individuals, both variables showed a higher estimated risk of mortality in patients, although without statistical association (P > 0.05). Conclusion We infer that two possible biomarkers (one immunological and one genetic) could be considered in association with gastric cancer in our population, which should be confirmed by subsequent studies involving a greater number of individuals.
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Tang C, Cheng X, Yu S, Wang Y, Hou J, Li Q, Shen Z, Liu T, Cui Y. Platelet-to-lymphocyte ratio and lymphocyte-to-white blood cell ratio predict the efficacy of neoadjuvant chemotherapy and the prognosis of locally advanced gastric cancer patients treated with the oxaliplatin and capecitabine regimen. Onco Targets Ther 2018; 11:7061-7075. [PMID: 30410363 PMCID: PMC6200072 DOI: 10.2147/ott.s176768] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background Many studies have discussed the relationship between routine blood parameters and the prognosis of gastric cancer patients; however, few studies focused on the association of routine blood parameters with the efficacy of neoadjuvant chemotherapy (NAC). Patients and methods We retrospectively collected routine blood parameters and other clinicopathological data of 104 patients with locally advanced gastric cancer (LAGC) who received the oxaliplatin and capecitabine regimen as NAC from June 2010 to March 2016. The objective response rate (ORR), pathological remission rate (pRR), overall survival (OS), and time to recurrence (TTR) were analyzed through different statistical methods, such as Chi-squared test, log-rank test, logistic regression, and Cox regression. Results In the multivariate analysis, a high platelet-to-lymphocyte ratio (PLR) (≥130.7) predicted a low ORR (OR =5.927, 95% CI: 2.184–16.089) and a low pRR (OR =8.343, 95% CI: 2.178–31.962), while a high lymphocyte-to-white blood cell ratio (LWR) (≥0.228) independently predicted a high ORR (OR =0.118, 95% CI: 0.031–0.448) and a high pRR (OR =0.096, 95% CI: 0.021–0.426). High lymphocyte level (≥1.750×109/L) was an independent predictor of long OS (HR =0.428, 95% CI: 0.190–0.964) and long TTR (HR =0.328, 95% CI: 0.156–0.690). High monocyte level (≥0.215×109/L) was associated with a high pRR (OR =0.072, 95% CI: 0.008–0.636) and a long OS (HR = 0.506, 95% CI: 0.257–0.997). Conclusion In patients with LAGC treated with the oxaliplatin and capecitabine regimen as NAC, a low PLR (<130.7) and a high LWR (≥0.228) independently predicted a high ORR and pRR. High monocyte level (≥0.215×109/L) was an independent predictor for a high pRR and long OS, while patients with high lymphocyte level (≥1.750×109/L) tended to have a long OS and TTR.
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Affiliation(s)
- Cheng Tang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China; ;
| | - Xi Cheng
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China; ;
| | - Shan Yu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China; ;
| | - Yan Wang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China; ;
| | - Jun Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qian Li
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China; ;
| | - Zhenbin Shen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China; ;
| | - Yuehong Cui
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China; ;
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Nebot-Bral L, Coutzac C, Kannouche PL, Chaput N. Why is immunotherapy effective (or not) in patients with MSI/MMRD tumors? Bull Cancer 2018; 106:105-113. [PMID: 30342749 DOI: 10.1016/j.bulcan.2018.08.007] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 08/02/2018] [Indexed: 12/26/2022]
Abstract
In the last few years, immunotherapy has revolutionized the oncology landscape by targeting the host immune system. Blocking immune checkpoints such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death-1 (PD-1) and its ligand (PD-L1 or B7-H1), has proven its efficacy in several solid cancers. Recently, several clinical studies have demonstrated a significant improvement in clinical response to the anti-PD-1-based immunotherapy in a subset of patients with microsatellite instability-high (MSI-H)/mismatch repair (MMR)-deficient tumors that accumulate short insertion/deletion mutations notably in coding microsatellites regions of the genome. Thus, the responsiveness of MSI cancers to immune checkpoint inhibitors can be explained by the increased rate of putative frameshift peptide neoantigens and the immunogenic tumor microenvironment. However, not all MSI tumors respond to immunotherapy. The current review will summarize how and why MMR deficiency has emerged as an important predictor of sensitivity for immunotherapy-based strategies. We will also discuss tumor-cell intrinsic genetic and immune-related features of MSI tumors that can modulate immune checkpoint blockade response and explain primary and/or acquired resistance to anti-PD-1 therapy. Finally, we will also discuss about emerging scores which can define more precisely the immune context of the tumor microenvironment and thus better evaluate prognosis and predict response to Immune Checkpoint Blockade.
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Affiliation(s)
- Laetitia Nebot-Bral
- UMR8200 - CNRS, stabilité génétique et oncogenèse, équipe labellisée ligue nationale contre le cancer, 94805, Villejuif, France; Gustave-Roussy Cancer Campus, 94805, Villejuif, France; Université Paris Saclay, 91400 Paris Sud - Orsay, France
| | - Clelia Coutzac
- Hôpital européen George-Pompidou, service de gastroentérologie et cancérologie digestive, 75015 Paris, France; Université Paris-Descartes, faculté de médecine, 75006, Paris, France
| | - Patricia L Kannouche
- UMR8200 - CNRS, stabilité génétique et oncogenèse, équipe labellisée ligue nationale contre le cancer, 94805, Villejuif, France; Gustave-Roussy Cancer Campus, 94805, Villejuif, France; Université Paris Saclay, 91400 Paris Sud - Orsay, France.
| | - Nathalie Chaput
- UMR8200 - CNRS, stabilité génétique et oncogenèse, équipe labellisée ligue nationale contre le cancer, 94805, Villejuif, France; Gustave-Roussy Cancer Campus, Laboratory of Immunomonitoring in Oncology, CNRS-UMS 3655 and Inserm-US23, 94805, Villejuif, France; University Paris-Saclay, faculté de pharmacie, Chatenay-Malabry 92296, France.
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Räihä MR, Puolakkainen PA. Tumor-associated macrophages (TAMs) as biomarkers for gastric cancer: A review. Chronic Dis Transl Med 2018; 4:156-163. [PMID: 30276362 PMCID: PMC6160505 DOI: 10.1016/j.cdtm.2018.07.001] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Indexed: 02/07/2023] Open
Abstract
Gastric adenocarcinoma is one of the most common types of cancer worldwide, with an incidence of a million new cases annually. In addition to having a high mortality rate due to often delayed detection and its poor response to cancer therapy, it also spreads aggressively. Inflammation has been shown to play a role in carcinogenesis. Consequently, macrophages are important in phagocytosis, antigen presenting and producing cytokines and growth factors. As a response to microenvironmental signals, they may polarize into tumor resisting M1 or tumor promoting M2 macrophages. Recently, studies have indicated that M2-type macrophage resembling tumor-associated macrophages (TAMs) might be used as an independent prognostic factor for gastric cancer. This review will discuss the possible use of TAMs as prognostic tools for gastric cancer and whether they are suitable for use in clinical environment.
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Affiliation(s)
- Meri R Räihä
- Department of Surgery, Helsinki University Hospital and University of Helsinki, Helsinki 00014, Finland
| | - Pauli A Puolakkainen
- Department of Surgery, Helsinki University Hospital and University of Helsinki, Helsinki 00014, Finland
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Lazăr DC, Avram MF, Romoșan I, Cornianu M, Tăban S, Goldiș A. Prognostic significance of tumor immune microenvironment and immunotherapy: Novel insights and future perspectives in gastric cancer. World J Gastroenterol 2018; 24:3583-3616. [PMID: 30166856 PMCID: PMC6113718 DOI: 10.3748/wjg.v24.i32.3583] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Revised: 06/05/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Despite a decrease in gastric cancer incidence, the development of novel biologic agents and combined therapeutic strategies, the prognosis of gastric cancer remains poor. Recently, the introduction of modern immunotherapy, especially using immune checkpoint inhibitors, led to an improved prognosis in many cancers. The use of immunotherapy was also associated with manageable adverse event profiles and promising results in the treatment of patients with gastric cancer, especially in heavily pretreated patients. These data have led to an accelerated approval of some checkpoint inhibitors in this setting. Understanding the complex relationship between the host immune microenvironment and tumor and the immune escape phenomenon leading to cancer occurrence and progression will subsequently lead to the identification of prognostic immune markers. Furthermore, this understanding will result in the discovery of both new mechanisms for blocking tumor immunosuppressive signals and pathways to stimulate the local immune response by targeting and modulating different subsets of immune cells. Due to the molecular heterogeneity of gastric cancers associated with different clinico-biologic parameters, immune markers expression and prognosis, novel immunotherapy algorithms should be personalized and addressed to selected subsets of gastric tumors, which have been proven to elicit the best clinical responses. Future perspectives in the treatment of gastric cancer include tailored dual immunotherapies or a combination of immunotherapy with other targeted agents with synergistic antitumor effects.
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Affiliation(s)
- Daniela Cornelia Lazăr
- Department of Internal Medicine I, University Medical Clinic, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
| | - Mihaela Flavia Avram
- Department of Surgery X, 1st Surgery Clinic, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
| | - Ioan Romoșan
- Department of Internal Medicine I, University Medical Clinic, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
| | - Mărioara Cornianu
- Department of Pathology, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
| | - Sorina Tăban
- Department of Pathology, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
| | - Adrian Goldiș
- Department of Gastroenterology and Hepatology, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
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Shen M, Kang Y. Complex interplay between tumor microenvironment and cancer therapy. Front Med 2018; 12:426-439. [PMID: 30097962 DOI: 10.1007/s11684-018-0663-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 07/05/2018] [Indexed: 12/16/2022]
Abstract
Tumor microenvironment (TME) is comprised of cellular and non-cellular components that exist within and around the tumor mass. The TME is highly dynamic and its importance in different stages of cancer progression has been well recognized. A growing body of evidence suggests that TME also plays pivotal roles in cancer treatment responses. TME is significantly remodeled upon cancer therapies, and such change either enhances the responses or induces drug resistance. Given the importance of TME in tumor progression and therapy resistance, strategies that remodel TME to improve therapeutic responses are under developing. In this review, we provide an overview of the essential components in TME and the remodeling of TME in response to anti-cancer treatments. We also summarize the strategies that aim to enhance therapeutic efficacy by modulating TME.
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Affiliation(s)
- Minhong Shen
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA
| | - Yibin Kang
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA.
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Kim Y, Wen X, Bae JM, Kim JH, Cho NY, Kang GH. The distribution of intratumoral macrophages correlates with molecular phenotypes and impacts prognosis in colorectal carcinoma. Histopathology 2018; 73:663-671. [DOI: 10.1111/his.13674] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Accepted: 06/12/2018] [Indexed: 12/30/2022]
Affiliation(s)
- Younghoon Kim
- Laboratory of Epigenetics; Cancer Research Institute; Seoul National University College of Medicine; Seoul South Korea
- Department of Pathology; Seoul National University College of Medicine; Seoul South Korea
| | - Xianyu Wen
- Laboratory of Epigenetics; Cancer Research Institute; Seoul National University College of Medicine; Seoul South Korea
- Department of Pathology; Seoul National University College of Medicine; Seoul South Korea
| | - Jeong M Bae
- Laboratory of Epigenetics; Cancer Research Institute; Seoul National University College of Medicine; Seoul South Korea
- Department of Pathology; Seoul National University Hospital; Seoul South Korea
| | - Jung H Kim
- Laboratory of Epigenetics; Cancer Research Institute; Seoul National University College of Medicine; Seoul South Korea
- Department of Pathology; Seoul National University Hospital; Seoul South Korea
| | - Nam-Yun Cho
- Laboratory of Epigenetics; Cancer Research Institute; Seoul National University College of Medicine; Seoul South Korea
| | - Gyeong H Kang
- Laboratory of Epigenetics; Cancer Research Institute; Seoul National University College of Medicine; Seoul South Korea
- Department of Pathology; Seoul National University College of Medicine; Seoul South Korea
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Huang X, Pan Y, Ma J, Kang Z, Xu X, Zhu Y, Chen J, Zhang W, Chang W, Zhu J. Prognostic significance of the infiltration of CD163 + macrophages combined with CD66b + neutrophils in gastric cancer. Cancer Med 2018; 7:1731-1741. [PMID: 29573574 PMCID: PMC5943426 DOI: 10.1002/cam4.1420] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 02/01/2018] [Accepted: 02/05/2018] [Indexed: 12/28/2022] Open
Abstract
The polarization of tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs), especially from the antitumoral phenotype to the protumoral phenotype under certain conditions, has an important influence on the progression of tumors. However, the interactions and combined prognosis of these cells are poorly known. Here, we detected the infiltration of CD68+ TAMs, CD163+ TAMs, and CD66b+ TANs in the specimens from 662 patients with GC by immunohistochemistry. The results showed that the infiltration of each of CD163+ , CD68+ , and CD66b+ cells in GC tissue was significantly increased and independently associated with GC prognosis. Strong collinearity (r = 0.690, P < 0.001) was found between the infiltration of CD163+ and CD68+ cells in GC, and multivariate Cox analysis confirmed the infiltration of CD163+ cells was a better predictor for prognosis than that of CD68+ cells. The combination of the infiltration of CD163+ and CD66b+ cells provided more accurate survival prediction than any individual marker. Patient subgroups with CD66blow CD163low (hazard ratio (HR) = 2.161; 95% confidence interval (CI) = 1.266-3.688; P < 0.001), CD66bhigh CD163high (HR = 3.575; 95% CI = 2.155-5.933; P < 0.001), and CD66blow CD163high (HR = 7.514; 95% CI = 4.583-12.312; P < 0.001) were gradually associated with shorter DFS when compared with the subgroup with CD66bhigh CD163low . The similar result was also for DSS among the subgroups. Moreover, the two-marker model could more effectively discriminate the prognosis among the patients with chemotherapy than that among those without chemotherapy. We concluded that CD163+ TAMs were a more valuable prognostic marker than CD68+ TAMs, and CD163+ TAMs combined with CD66b+ TANs could more precisely predict the prognosis of patients with GC.
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Affiliation(s)
- Xiaopei Huang
- Department of Health ToxicologySecond Military Medical UniversityShanghai 200433China
- Department of Environmental HygieneSecond Military Medical UniversityShanghai 200433China
| | - Yamin Pan
- The First Department of EndoscopyShuguang HospitalShanghai University of Traditional Chinese MedicineShanghai 201203China
| | - Jun Ma
- Department of Colorectal SurgeryChanghai HospitalSecond Military Medical UniversityShanghai 200433China
| | - Zhengchun Kang
- Department of Colorectal SurgeryChanghai HospitalSecond Military Medical UniversityShanghai 200433China
| | - Xiaowen Xu
- Department of Colorectal SurgeryChanghai HospitalSecond Military Medical UniversityShanghai 200433China
| | - Yan Zhu
- Department of PathologyChanghai HospitalSecond Military Medical UniversityShanghai 200433China
| | - Jikuai Chen
- Department of Health ToxicologySecond Military Medical UniversityShanghai 200433China
| | - Wei Zhang
- Department of Colorectal SurgeryChanghai HospitalSecond Military Medical UniversityShanghai 200433China
| | - Wenjun Chang
- Department of Environmental HygieneSecond Military Medical UniversityShanghai 200433China
| | - Jiangbo Zhu
- Department of Health ToxicologySecond Military Medical UniversityShanghai 200433China
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Narasimhan PB, Akabas L, Tariq S, Huda N, Bennuru S, Sabzevari H, Hofmeister R, Nutman TB, Tolouei Semnani R. Similarities and differences between helminth parasites and cancer cell lines in shaping human monocytes: Insights into parallel mechanisms of immune evasion. PLoS Negl Trop Dis 2018; 12:e0006404. [PMID: 29668679 PMCID: PMC5927465 DOI: 10.1371/journal.pntd.0006404] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 04/30/2018] [Accepted: 03/22/2018] [Indexed: 12/24/2022] Open
Abstract
A number of features at the host-parasite interface are reminiscent of those that are also observed at the host-tumor interface. Both cancer cells and parasites establish a tissue microenvironment that allows for immune evasion and may reflect functional alterations of various innate cells. Here, we investigated how the phenotype and function of human monocytes is altered by exposure to cancer cell lines and if these functional and phenotypic alterations parallel those induced by exposure to helminth parasites. Thus, human monocytes were exposed to three different cancer cell lines (breast, ovarian, or glioblastoma) or to live microfilariae (mf) of Brugia malayi-a causative agent of lymphatic filariasis. After 2 days of co-culture, monocytes exposed to cancer cell lines showed markedly upregulated expression of M1-associated (TNF-α, IL-1β), M2-associated (CCL13, CD206), Mreg-associated (IL-10, TGF-β), and angiogenesis associated (MMP9, VEGF) genes. Similar to cancer cell lines, but less dramatically, mf altered the mRNA expression of IL-1β, CCL13, TGM2 and MMP9. When surface expression of the inhibitory ligands PDL1 and PDL2 was assessed, monocytes exposed to both cancer cell lines and to live mf significantly upregulated PDL1 and PDL2 expression. In contrast to exposure to mf, exposure to cancer cell lines increased the phagocytic ability of monocytes and reduced their ability to induce T cell proliferation and to expand Granzyme A+ CD8+ T cells. Our data suggest that despite the fact that helminth parasites and cancer cell lines are extraordinarily disparate, they share the ability to alter the phenotype of human monocytes.
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Affiliation(s)
- Prakash Babu Narasimhan
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America
| | - Leor Akabas
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America
| | - Sameha Tariq
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America
| | - Naureen Huda
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America
| | - Sasisekhar Bennuru
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America
| | - Helen Sabzevari
- EMD Serono Research and Development Institute, Billerica, MA, United States of America
| | - Robert Hofmeister
- EMD Serono Research and Development Institute, Billerica, MA, United States of America
| | - Thomas B. Nutman
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America
| | - Roshanak Tolouei Semnani
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America
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MiRNAs at the Crossroads between Innate Immunity and Cancer: Focus on Macrophages. Cells 2018; 7:cells7020012. [PMID: 29419779 PMCID: PMC5850100 DOI: 10.3390/cells7020012] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 02/01/2018] [Accepted: 02/06/2018] [Indexed: 12/12/2022] Open
Abstract
Innate immune cells form an integrative component of the tumor microenvironment (TME), which can control or prevent tumor initiation and progression, due to the simultaneous processing of both anti- and pro-growth signals. This decision-making process is a consequence of gene expression changes, which are in part dependent on post-transcriptional regulatory mechanisms. In this context, microRNAs have been shown to regulate both recruitment and activation of specific tumor-associated immune cells in the TME. This review aims to describe the most important microRNAs that target cancer-related innate immune pathways. The role of exosomal microRNAs in tumor progression and microRNA-based therapeutic strategies are also discussed.
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Li S, Xu F, Zhang J, Wang L, Zheng Y, Wu X, Wang J, Huang Q, Lai M. Tumor-associated macrophages remodeling EMT and predicting survival in colorectal carcinoma. Oncoimmunology 2017; 7:e1380765. [PMID: 29416940 DOI: 10.1080/2162402x.2017.1380765] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 09/09/2017] [Accepted: 09/13/2017] [Indexed: 12/23/2022] Open
Abstract
The immune contexture, a composition of the tumor microenvironment, plays multiple important roles in cancer stem cell (CSC) and epithelial-mesenchymal transition (EMT), and hence critically influences tumor initiation, progression and patient outcome. Tumor-associated macrophages (TAMs) are abundant in immune contexture, however their roles in CSC, EMT and prognosis of colorectal cancer (CRC) have not been elucidated. In 419 colorectal carcinomas, immune cell types (CD68+ macrophages, CD3+, CD4+ or CD8+ T lymphocytes, CD20+ B lymphocytes), EMT markers (E-cadherin and Snail) as well as the stem cell marker (CD44v6) were detected in tumor center (TC) and tumor invasive front (TF) respectively by immunohistochemistry. Tumor buds, that represent EMT phenotype, were also counted. It was found CD68+ macrophages were the most infiltrating immune cells in CRC. By correlation analysis, more CD68+TF macrophages were associated with more CD44v6 expression (p < 0.001), lower SnailTF expression (p = 0.08) and fewer tumor buds (p < 0.001). More CD68+TF macrophages were significantly related to more CD3+TF T lymphocytes (p = 0.002), CD8+TF T lymphocytes (p < 0.001) and CD20+TF B lymphocytes counts (p = 0.004). Strong CD68+TF macrophages infiltration also predicted long term overall survival. CRC patients with more tumor buds had worse survival. However, strong CD68+TF macrophages infiltration could reverse the unfavorable results since patients with more tumor buds but increasing CD68+TF macrophages infiltration had the favorable outcome, similar to lower tumor buds groups. This study provided direct morphological evidence that tumor-associated macrophages in the invasive front play critical roles in fighting with the unfavorable results of tumor buds, thus resulting favorable outcomes for CRC patients.
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Affiliation(s)
- Si Li
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Fangying Xu
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jing Zhang
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Lili Wang
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yang Zheng
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xuesong Wu
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jing Wang
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Qiong Huang
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Maode Lai
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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Zhang Y, Zhou N, Yu X, Zhang X, Li S, Lei Z, Hu R, Li H, Mao Y, Wang X, Zhang J, Li Y, Guo H, Irwin DM, Niu G, Tan H. Tumacrophage: macrophages transformed into tumor stem-like cells by virulent genetic material from tumor cells. Oncotarget 2017; 8:82326-82343. [PMID: 29137267 PMCID: PMC5669893 DOI: 10.18632/oncotarget.19320] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 06/20/2017] [Indexed: 02/06/2023] Open
Abstract
Tumor-associated macrophages are regarded as tumor-enhancers as they have key roles in the subversion of adaptive immunity and in inflammatory circuits that promote tumor progression. Here, we show that cancer cells can subvert macrophages yielding cells that have gained pro-tumor functions. When macrophages isolated from mice or humans are co-cultured with dead cancer cell line cells, induced to undergo apoptosis to mimic chemotherapy, up-regulation of pro-tumor gene expression was identified. Phagocytosis of apoptotic cancer cells by macrophages resulted in their transformation into tumor stem (initiating)-like cells, as indicated by the expression of epithelial markers (e.g., cytokeratin) and stem cell markers (e.g., Oct4) and their capability to differentiate in vitro and self-renew in serum-free media. Moreover, we identified a subset of monocytes/macrophages cells in the blood of cancer (breast, ovarian and colorectal) patients undergoing chemotherapy that harbor tumor transcripts. Our findings uncover a new role for macrophages in tumor development, where they can be transformed into tumor-like cells, potentially by horizontal gene transfer of tumor-derived genes, thus, by taking advantage of chemotherapy, these transformed macrophages promote tumor metastasis by escaping immune surveillance.
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Affiliation(s)
- Yizhuang Zhang
- Department of Pharmacology, Peking University, Beijing, China
| | - Na Zhou
- Department of Pharmacology, Peking University, Beijing, China
| | - Xiuyan Yu
- Department of Pharmacology, Peking University, Beijing, China
| | - Xuehui Zhang
- Department of Pharmacology, Peking University, Beijing, China
| | - Shanxin Li
- Department of Pharmacology, Peking University, Beijing, China
| | - Zhen Lei
- N & N Genetech Company, Ltd., Beijing, China
| | - Ruobi Hu
- Department of Pharmacology, Peking University, Beijing, China
| | - Hui Li
- Department of Pharmacology, Peking University, Beijing, China
| | - Yiqing Mao
- Department of Pharmacology, Peking University, Beijing, China
| | - Xi Wang
- Department of Pharmacology, Peking University, Beijing, China
| | - Jinshu Zhang
- Department of Clinical Laboratory, The 305 Hospital of People’s Liberation Army, Beijing, China
| | - Yuan Li
- Department of Gynaecology and Obstetrics, Peking University Third Hospital, Beijing, China
| | - Hongyan Guo
- Department of Gynaecology and Obstetrics, Peking University Third Hospital, Beijing, China
| | - David M. Irwin
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Gang Niu
- N & N Genetech Company, Ltd., Beijing, China
| | - Huanran Tan
- Department of Pharmacology, Peking University, Beijing, China
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Jiang W, Liu K, Guo Q, Cheng J, Shen L, Cao Y, Wu J, Shi J, Cao H, Liu B, Tao K, Wang G, Cai K. Tumor-infiltrating immune cells and prognosis in gastric cancer: a systematic review and meta-analysis. Oncotarget 2017; 8:62312-62329. [PMID: 28977947 PMCID: PMC5617507 DOI: 10.18632/oncotarget.17602] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 04/11/2017] [Indexed: 12/29/2022] Open
Abstract
Tumor-infiltrating immune cells are a pivotal component of the tumor microenvironment (TME), but their indicative role remains poorly defined. A meta-analysis was performed to reveal the prognostic efficiency of tumor-infiltrating immune cells in gastric cancer (GC). By searching PubMed and Embase, we identified a total of 35 eligible articles that involved 4888 patients. Random or fixed effect models were employed to extract pooled hazard ratios (HRs) with 95% confidence intervals (CIs). Our results indicated that high CD3+ lymphocyte infiltration in all the locations (AG), the tumor nest (TN), and the tumor stroma (TS) predicted better overall survival (OS) (HR=0.71, 95% CI=0.57-0.90; HR=0.58, 95% CI=0.42-0.80; and HR=0.50, 95% CI=0.37-0.68, respectively). CD8+ T cell infiltration in AG and FoxP3+ regulatory T cells (Tregs) in the tumor invasive margin (TM) were also associated with improved OS (HR=0.90, 95% CI=0.83-0.97; HR=0.65, 95% CI=0.48-0.87, respectively). However, contrasting results were found in the macrophage subset, with M2 in AG (HR=1.45, 95% CI=1.13-1.86) and the TN (HR=1.67, 95% CI=1.12-2.48) associated with worse OS. In summary, the combination of the densities and locations of tumor-infiltrating immune cells can be useful for predicting survival for GC patients, but additional research is needed to reinforce the reliability of this study's conclusions.
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Affiliation(s)
- Wen Jiang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ke Liu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qing Guo
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ji Cheng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liming Shen
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yinghao Cao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Wu
- MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Maternal and Child Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianguo Shi
- Department of Gastrointestinal Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Heng Cao
- Department of Gastrointestinal Surgery, Xinyang Central Hospital, Xinyang, China
| | - Bo Liu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guobin Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kailin Cai
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Nemoto T, Shibata Y, Inoue S, Igarashi A, Tokairin Y, Yamauchi K, Kimura T, Sato M, Sato K, Nakano H, Abe S, Nishiwaki M, Kobayashi M, Yang S, Minegishi Y, Furuyama K, Machida H, Kubota I. MafB silencing in macrophages does not influence the initiation and growth of lung cancer induced by urethane. EXCLI JOURNAL 2017; 16:914-920. [PMID: 28900373 PMCID: PMC5579402 DOI: 10.17179/excli2017-325] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 05/22/2017] [Indexed: 12/26/2022]
Abstract
An increased number of tumor-associated macrophages (TAMs) that exhibit the M2 macrophage phenotype is related to poorer prognosis in cancer patients. MafB is a transcription factor regulating the differentiation of macrophages. However, involvement of MafB for the development of TAMs is unknown. This study was designed to investigate the role of MafB in a murine urethane-induced lung cancer model. Urethane was injected intraperitoneally into wild-type and dominant-negative MafB transgenic mice. Twenty-four weeks later, mice were sacrificed and their lungs removed for pathological analysis. The numbers and mean areas of lung cancer were evaluated. In addition, the numbers of Mac-3-positive macrophages were evaluated in each tumor. The numbers and mean areas of lung cancer induced by urethane administration were not significantly different between wild-type and dominant-negative MafB transgenic mice. The numbers of TAMs in lung cancer tissue were not significantly different between the two groups. MafB silencing using dominant-negative MafB did not influence the initiation and growth of lung cancer in mice exposed to urethane. These data suggest that MafB may not be related to the development of TAMs.
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Affiliation(s)
- Takako Nemoto
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Yoko Shibata
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Sumito Inoue
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Akira Igarashi
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Yoshikane Tokairin
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Keiko Yamauchi
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Tomomi Kimura
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Masamichi Sato
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Kento Sato
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Hiroshi Nakano
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Shuichi Abe
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Michiko Nishiwaki
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Maki Kobayashi
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Sujeong Yang
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Yukihiro Minegishi
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Kodai Furuyama
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Hiroyoshi Machida
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
| | - Isao Kubota
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan
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Zheng X, Song X, Shao Y, Xu B, Chen L, Zhou Q, Hu W, Zhang D, Wu C, Tao M, Zhu Y, Jiang J. Prognostic role of tumor-infiltrating lymphocytes in gastric cancer: a meta-analysis. Oncotarget 2017; 8:57386-57398. [PMID: 28915679 PMCID: PMC5593650 DOI: 10.18632/oncotarget.18065] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 04/26/2017] [Indexed: 12/26/2022] Open
Abstract
Background In patients with gastric cancer, the prognostic value of tumor-infiltrating lymphocytes (TILs) is still controversial. A meta-analysis was performed to evaluate the prognostic value of TILs in gastric cancer. Materials and methods We identify studies from PubMed, Embase and the Cochrane Library to assess the prognostic effect of TILs in patients with gastric cancer. Fixed-effects models or random-effects models were used estimate the pooled hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS), which depend on the heterogeneity. Results A total of 31 observational studies including 4,185 patients were enrolled. For TILs subsets, the amount of CD8+, FOXP3+, CD3+, CD57+, CD20+, CD45RO+, Granzyme B+ and T-bet+ lymphocytes was significantly associated with improved survival (P < 0.05); moreover, the amount of CD3+ TILs in intra-tumoral compartment (IT) was the most significant prognostic marker (pooled HR = 0.52; 95% CI = 0.43–0.63; P < 0.001). However, CD4+ TILs was not statistically associated with patients’ survival. FOXP3+ TILs showed bidirectional prognostic roles which had positive effect in IT (pooled HR = 1.57; 95% CI = 1.04–2.37; P = 0.033) and negative effect in extra-tumoral compartment (ET) (pooled HR = 0.76; 95% CI = 0.60–0.96; P = 0.022). Conclusions This meta-analysis suggests that some TIL subsets could serve as prognostic biomarkers in gastric cancer. High-quality randomized controlled trials are needed to decide if these TILs could serve as targets for immunotherapy in gastric cancer.
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Affiliation(s)
- Xiao Zheng
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou 213003, People's Republic of China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, People's Republic of China.,Institute of Cell Therapy, Soochow University, Changzhou 213003, People's Republic of China
| | - Xing Song
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, People's Republic of China
| | - Yingjie Shao
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, People's Republic of China
| | - Bin Xu
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou 213003, People's Republic of China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, People's Republic of China.,Institute of Cell Therapy, Soochow University, Changzhou 213003, People's Republic of China
| | - Lujun Chen
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou 213003, People's Republic of China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, People's Republic of China.,Institute of Cell Therapy, Soochow University, Changzhou 213003, People's Republic of China
| | - Qi Zhou
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, People's Republic of China
| | - Wenwei Hu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, People's Republic of China
| | - Dachuan Zhang
- Department of Pathology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, People's Republic of China
| | - Changping Wu
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou 213003, People's Republic of China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, People's Republic of China.,Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, People's Republic of China
| | - Min Tao
- Institute of Cell Therapy, Soochow University, Changzhou 213003, People's Republic of China
| | - Yibei Zhu
- Institute of Cell Therapy, Soochow University, Changzhou 213003, People's Republic of China
| | - Jingting Jiang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou 213003, People's Republic of China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, People's Republic of China.,Institute of Cell Therapy, Soochow University, Changzhou 213003, People's Republic of China
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M2 macrophage is the predominant phenotype in airways inflammatory lesions in patients with granulomatosis with polyangiitis. Arthritis Res Ther 2017; 19:100. [PMID: 28521792 PMCID: PMC5437644 DOI: 10.1186/s13075-017-1310-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 05/02/2017] [Indexed: 01/13/2023] Open
Abstract
Background Macrophages may present two distinct phenotypes indicated as M1 and M2 under different stimuli. M1 and M2 macrophages have divergent functions that range from enhancement of inflammation for M1 to tissue repair and remodeling for M2 macrophages. The objective of this study was to evaluate the distribution of M1 and M2 macrophage phenotypes in biopsies from the airways of patients with active granulomatosis with polyangiitis (GPA) and to analyze their associations with T and B cells in those biopsies, and with nasal carriage of Staphylococcus aureus, disease parameters and therapy. Methods Consecutive GPA patients (n = 35) with active airway disease, who underwent respiratory tract biopsy were included. Immunohistochemical evaluation was performed to assess the distribution of macrophages and T and B cells using the markers CD68, CD3 and CD20, respectively. CD86 was used as the M1 marker and CD163 as the M2 marker while Tbet and GATA-3 were used as Th1 and Th2 markers, respectively. At the time of the biopsy patients were assessed for nasal carriage of Staphylococcus aureus and treatment. Results Percentages of macrophages and T cells were significantly higher than those of B cells in lesional tissue from the respiratory tract in GPA. M2 macrophages and Th2 cells were more frequent than M1 macrophages (p = 0.0007) and Th1 cells (p < 0.0001), respectively. Percentages of T cells were higher in nose biopsies than in biopsies from other sites (p = 0.021); macrophages and CD163+ macrophages were more predominant in biopsy sites other than the nose (p = 0.039 and p = 0.012, respectively). Carriage of Staphylococcus aureus was associated with higher T cell scores (p = 0.014). The frequency of macrophages, especially M2 macrophages, was higher in GPA patients treated with immunosuppressive agents (p = 0.010); daily prednisolone dose was positively correlated with all macrophage markers. However, in multivariate analysis no independent associations were found between disease parameters and therapy with macrophage markers or T cells. Conclusion In GPA, M2 is the predominant macrophage phenotype in the respiratory tract. Although some associations were observed between macrophages and T cells with therapy and nasal carriage of Staphylococcus aureus, they were not independently significant in multivariate analysis. Electronic supplementary material The online version of this article (doi:10.1186/s13075-017-1310-4) contains supplementary material, which is available to authorized users.
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Gao Y, Wang Z, Hao Q, Li W, Xu Y, Zhang J, Zhang W, Wang S, Liu S, Li M, Xue X, Zhang W, Zhang C, Zhang Y. Loss of ERα induces amoeboid-like migration of breast cancer cells by downregulating vinculin. Nat Commun 2017; 8:14483. [PMID: 28266545 PMCID: PMC5344302 DOI: 10.1038/ncomms14483] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 12/20/2016] [Indexed: 12/16/2022] Open
Abstract
Oestrogen receptor alpha (ERα) is a well-known target of endocrine therapy for ERα-positive breast cancer. ERα-negative cells, which are enriched during endocrine therapy, are associated with metastatic relapse. Here we determine that loss of ERα in the invasive front and in lymph node metastasis in human breast cancer is significantly correlated with lymphatic metastasis. Using in vivo and in vitro experiments, we demonstrate that ERα inhibits breast cancer metastasis. Furthermore, we find that ERα is a novel regulator of vinculin expression in breast cancer. Notably, ERα suppresses the amoeboid-like movement of breast cancer cells by upregulating vinculin in 3D matrix, which in turn promotes cell–cell and cell–matrix adhesion and inhibits the formation of amoeboid-like protrusions. A positive association between ERα and vinculin expression is found in human breast cancer tissues. The results show that ERα inhibits breast cancer metastasis and suggest that ERα suppresses cell amoeboid-like movement by upregulating vinculin. Estrogen receptor alpha (ERα)-negative cells, which are enriched during endocrine therapy, are associated with metastatic relapse of breast cancer. Here the authors show that ERα inhibits breast cancer metastasis and suggest that ERα suppresses the amoeboid-like migration of breast cancer cells by upregulating vinculin.
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Affiliation(s)
- Yuan Gao
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Zhaowei Wang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Qiang Hao
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Weina Li
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Yujin Xu
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Juliang Zhang
- Department of Vascular and Endocrine Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China
| | - Wangqian Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Shuning Wang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Shuo Liu
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Meng Li
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Xiaochang Xue
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Wei Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Cun Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Yingqi Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
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Yang L, Zhang Y. Tumor-associated macrophages: from basic research to clinical application. J Hematol Oncol 2017; 10:58. [PMID: 28241846 PMCID: PMC5329931 DOI: 10.1186/s13045-017-0430-2] [Citation(s) in RCA: 639] [Impact Index Per Article: 79.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 02/23/2017] [Indexed: 02/07/2023] Open
Abstract
The fact that various immune cells, including macrophages, can be found in tumor tissues has long been known. With the introduction of concept that macrophages differentiate into a classically or alternatively activated phenotype, the role of tumor-associated macrophages (TAMs) is now beginning to be elucidated. TAMs act as "protumoral macrophages," contributing to disease progression. TAMs can promote initiation and metastasis of tumor cells, inhibit antitumor immune responses mediated by T cells, and stimulate tumor angiogenesis and subsequently tumor progression. As the relationship between TAMs and malignant tumors becomes clearer, TAMs are beginning to be seen as potential biomarkers for diagnosis and prognosis of cancers, as well as therapeutic targets in these cases. In this review, we will discuss the origin, polarization, and role of TAMs in human malignant tumors, as well as how TAMs can be used as diagnostic and prognostic biomarkers and therapeutic targets of cancer in clinics.
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Affiliation(s)
- Li Yang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou, 450052, Henan Province, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou, 450052, Henan Province, China
| | - Yi Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou, 450052, Henan Province, China.
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou, 450052, Henan Province, China.
- School of Life Science, Zhengzhou University, No.100 Kexue Road, Zhengzhou, 450001, Henan Province, China.
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78495111110.1038/nrclinonc.2016.217" />
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