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Kumagai S, Itahashi K, Nishikawa H. Regulatory T cell-mediated immunosuppression orchestrated by cancer: towards an immuno-genomic paradigm for precision medicine. Nat Rev Clin Oncol 2024; 21:337-353. [PMID: 38424196 DOI: 10.1038/s41571-024-00870-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/12/2024] [Indexed: 03/02/2024]
Abstract
Accumulating evidence indicates that aberrant signalling stemming from genetic abnormalities in cancer cells has a fundamental role in their evasion of antitumour immunity. Immune escape mechanisms include enhanced expression of immunosuppressive molecules, such as immune-checkpoint proteins, and the accumulation of immunosuppressive cells, including regulatory T (Treg) cells, in the tumour microenvironment. Therefore, Treg cells are key targets for cancer immunotherapy. Given that therapies targeting molecules predominantly expressed by Treg cells, such as CD25 or GITR, have thus far had limited antitumour efficacy, elucidating how certain characteristics of cancer, particularly genetic abnormalities, influence Treg cells is necessary to develop novel immunotherapeutic strategies. Hence, Treg cell-targeted strategies based on the particular characteristics of cancer in each patient, such as the combination of immune-checkpoint inhibitors with molecularly targeted agents that disrupt the immunosuppressive networks mediating Treg cell recruitment and/or activation, could become a new paradigm of cancer therapy. In this Review, we discuss new insights on the mechanisms by which cancers generate immunosuppressive networks that attenuate antitumour immunity and how these networks confer resistance to cancer immunotherapy, with a focus on Treg cells. These insights lead us to propose the concept of 'immuno-genomic precision medicine' based on specific characteristics of cancer, especially genetic profiles, that correlate with particular mechanisms of tumour immune escape and might, therefore, inform the optimal choice of immunotherapy for individual patients.
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Affiliation(s)
- Shogo Kumagai
- Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo, Japan
- Division of Cancer Immunology, Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Chiba, Japan
- Division of Cellular Signalling, Research Institute, National Cancer Center, Tokyo, Japan
| | - Kota Itahashi
- Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo, Japan
- Division of Cancer Immunology, Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Chiba, Japan
| | - Hiroyoshi Nishikawa
- Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo, Japan.
- Division of Cancer Immunology, Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Chiba, Japan.
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
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Kim H, Heo YJ, Cho YA, Kang SY, Ahn S, Kim KM. Tumor immune microenvironment is influenced by frameshift mutations and tumor mutational burden in gastric cancer. Clin Transl Oncol 2021; 24:556-567. [PMID: 34767183 DOI: 10.1007/s12094-021-02714-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/23/2021] [Indexed: 02/05/2023]
Abstract
PURPOSE Immunoscore can effectively predict prognosis in patients with colon cancer; however, its clinical application is limited. We modified the Immunoscore and created a tumor immune microenvironment (TIM) classification system for gastric carcinoma. Unlike previous studies that used small sample sizes or focused on particular immune-cell subtypes, our simplified system enables pathologists to classify gastric carcinomas intuitively using H&E-stained sections. METHODS Samples from 326 patients with advanced gastric carcinoma were reviewed and analyzed by pathologists using simple determination and digital image analysis. Comprehensive results of cancer-panel sequencing, Epstein-Barr‒virus (EBV) status, and PD-L1, HER2, ATM, PTEN, MET, FGFR2, and EGFR immunohistochemistry were evaluated with respect to the TIM class. RESULTS The TIM was classified as "hot" (n = 22), "immunosuppressed" (n = 178), "excluded" (n = 83), or "cold" (n = 43). TIM category was significantly associated with numbers of frameshift mutations (P < 0.001) and high tumor mutational burden (P < 0.004), and predicted overall survival. It was also significantly associated with age, histological type, degree of fibrosis, PD-L1 expression, loss of ATM and PTEN expression (P < 0.001), sex, EBV positivity, and HER2 overexpression (P < 0.04). "Hot" tumors were frequent in PD-L1 expressing and EBV-positive samples, and in those with ATM and PTEN loss. "Excluded" tumors were frequent in HER2-positive cases, whereas "cold" tumors were more frequent in younger patients with poorly cohesive histology and high fibrosis levels. CONCLUSIONS TIM classification system for gastric carcinoma has prognostic significance and results in classes that are associated with molecular characteristics.
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Affiliation(s)
- H Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Y J Heo
- The Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Y A Cho
- Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea
| | - S Y Kang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - S Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - K -M Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. .,The Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
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Senovilla L, Vacchelli E, Galon J, Adjemian S, Eggermont A, Fridman WH, Sautès-Fridman C, Ma Y, Tartour E, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: Prognostic and predictive value of the immune infiltrate in cancer. Oncoimmunology 2021; 1:1323-1343. [PMID: 23243596 PMCID: PMC3518505 DOI: 10.4161/onci.22009] [Citation(s) in RCA: 188] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Solid tumors are constituted of a variety of cellular components, including bona fide malignant cells as well as endothelial, structural and immune cells. On one hand, the tumor stroma exerts major pro-tumorigenic and immunosuppressive functions, reflecting the capacity of cancer cells to shape the microenvironment to satisfy their own metabolic and immunological needs. On the other hand, there is a component of tumor-infiltrating leucocytes (TILs) that has been specifically recruited in the attempt to control tumor growth. Along with the recognition of the critical role played by the immune system in oncogenesis, tumor progression and response to therapy, increasing attention has been attracted by the potential prognostic and/or predictive role of the immune infiltrate in this setting. Data from large clinical studies demonstrate indeed that a robust infiltration of neoplastic lesions by specific immune cell populations, including (but not limited to) CD8+ cytotoxic T lymphocytes, Th1 and Th17 CD4+ T cells, natural killer cells, dendritic cells, and M1 macrophages constitutes an independent prognostic indicator in several types of cancer. Conversely, high levels of intratumoral CD4+CD25+FOXP3+ regulatory T cells, Th2 CD4+ T cells, myeloid-derived suppressor cells, M2 macrophages and neutrophils have frequently been associated with dismal prognosis. So far, only a few studies have addressed the true predictive potential of TILs in cancer patients, generally comforting the notion that—at least in some clinical settings—the immune infiltrate can reliably predict if a specific patient will respond to therapy or not. In this Trial Watch, we will summarize the results of clinical trials that have evaluated/are evaluating the prognostic and predictive value of the immune infiltrate in the context of solid malignancies.
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Affiliation(s)
- Laura Senovilla
- Institut Gustave Roussy; Villejuif, France ; Université Paris-Sud/Paris XI; Orsay, France ; INSERM, U848; Villejuif, France
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Bruni D, Angell HK, Galon J. The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy. Nat Rev Cancer 2020; 20:662-680. [PMID: 32753728 DOI: 10.1038/s41568-020-0285-7] [Citation(s) in RCA: 1015] [Impact Index Per Article: 203.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/22/2020] [Indexed: 12/15/2022]
Abstract
The international American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) tumour-node-metastasis (TNM) staging system provides the current guidelines for the classification of cancer. However, among patients within the same stage, the clinical outcome can be very different. More recently, a novel definition of cancer has emerged, implicating at all stages a complex and dynamic interaction between tumour cells and the immune system. This has enabled the definition of the immune contexture, representing the pre-existing immune parameters associated with patient survival. Even so, the role of distinct immune cell types in modulating cancer progression is increasingly emerging. An immune-based assay named the 'Immunoscore' was defined to quantify the in situ T cell infiltrate and was demonstrated to be superior to the AJCC/UICC TNM classification for patients with colorectal cancer. This Review provides a broad overview of the main immune parameters positively or negatively shaping cancer development, including the Immunoscore, and their prognostic and predictive value. The importance of the immune system in cancer control is demonstrated by the requirement for a pre-existing intratumour adaptive immune response for effective immunotherapies, such as checkpoint inhibitors. Finally, we discuss how the combination of multiple immune parameters, rather than individual ones, might increase prognostic and/or predictive power.
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Affiliation(s)
- Daniela Bruni
- INSERM, Laboratory of Integrative Cancer Immunology; Équipe Labellisée Ligue Contre le Cancer; Sorbonne Université; Sorbonne Paris Cité; Université de Paris; Centre de Recherche des Cordeliers, Paris, France
| | - Helen K Angell
- Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, UK
| | - Jérôme Galon
- INSERM, Laboratory of Integrative Cancer Immunology; Équipe Labellisée Ligue Contre le Cancer; Sorbonne Université; Sorbonne Paris Cité; Université de Paris; Centre de Recherche des Cordeliers, Paris, France.
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Zhao YB, Yang SH, Shen J, Deng K, Li Q, Wang Y, Cui W, Ye H. Interaction between regulatory T cells and mast cells via IL-9 and TGF-β production. Oncol Lett 2020; 20:360. [PMID: 33133260 PMCID: PMC7590434 DOI: 10.3892/ol.2020.12224] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Accepted: 08/24/2020] [Indexed: 12/24/2022] Open
Abstract
Research on the immunosuppression of cancer cells has attracted much attention in recent years. The present study sought to provide a new strategy for tumor immunotherapy targeting mast cells by studying the mechanisms underlying mast cell function in cancer immunosuppression. Between January 2015 and December 2017, the tumor tissues of 40 patients with gastric cancer (GC) were collected and grouped in Lihuili Hospital of Ningbo City, China. Pathological sections were prepared and an immunofluorescence assay was performed to analyze the expression of forkhead Box Protein P3 (FOXP3), tryptase, TGFβ1, TGF-βR, IL-9, IL-9R and Oxford 40 ligand (OX40L). Then, the correlations between FOXP3 and tryptase, TGFβ1 and tryptase expression, and the expression of OX40L in patients with GC with different stages were analyzed. The results revealed that high levels of mast cells were present in patients GC, and tryptase and FOXP3 expressions were positively correlated. Mast cells regulate T regulatory (reg) cells in the gastric tumor microenvironment by secreting TGFβ1. Tregs, in turn, promote the survival of mast cells in the tumor microenvironment by producing IL-9. Furthermore, OX40L expression in mast cells was significantly associated with Tumor-Node-Metastasis staging of GC. Overall, the present study reported a positive feedback system that functions through TGFβ1 and IL-9 to allow cross-talk between Tregs and mast cells. Moreover, OX40L may be a potential target for the diagnosis and treatment of GC. These results may provide a new strategy for tumor immunotherapy targeting mast cells.
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Affiliation(s)
- Yi-Bin Zhao
- Department of Gastroenterology, Ningbo Medical Treatment Center, Lihuili Hospital, Ningbo, Zhejiang 315040, P.R. China
| | - Shao-Hui Yang
- Department of Gastroenterology, Ningbo Medical Treatment Center, Lihuili Hospital, Ningbo, Zhejiang 315040, P.R. China
| | - Jie Shen
- Department of Gastroenterology, Ningbo Medical Treatment Center, Lihuili Hospital, Ningbo, Zhejiang 315040, P.R. China
| | - Ke Deng
- Department of Gastroenterology, Ningbo Medical Treatment Center, Lihuili Hospital, Ningbo, Zhejiang 315040, P.R. China
| | - Qi Li
- Department of Gastroenterology, Ningbo Medical Treatment Center, Lihuili Hospital, Ningbo, Zhejiang 315040, P.R. China
| | - Yu Wang
- Department of Gastroenterology, Ningbo Medical Treatment Center, Lihuili Hospital, Ningbo, Zhejiang 315040, P.R. China
| | - Wei Cui
- Department of Gastroenterology, Ningbo Medical Treatment Center, Lihuili Hospital, Ningbo, Zhejiang 315040, P.R. China
| | - Hua Ye
- Department of Gastroenterology, Ningbo Medical Treatment Center, Lihuili Hospital, Ningbo, Zhejiang 315040, P.R. China
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Heo YJ, Lee T, Byeon SJ, Kim EJ, Shin HC, Kim B, Kang SY, Ha SY, Kim KM. Digital image analysis in pathologist-selected regions of interest predicts survival more accurately than whole-slide analysis: a direct comparison study in 153 gastric carcinomas. JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2020; 7:42-51. [PMID: 32885920 PMCID: PMC7737754 DOI: 10.1002/cjp2.179] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 07/15/2020] [Accepted: 07/20/2020] [Indexed: 12/24/2022]
Abstract
Automatic quantification of biomarkers such as tumor‐infiltrating lymphocytes and PD‐L1 is one of the most studied topics in digital pathology image analysis (DIA). However, direct comparison between the DIA of a whole‐slide image (WSI) and that of regions of interest (ROIs) chosen by pathologists has not been performed. In this study, we aimed to compare the prognostic value of tumor microenvironment markers CD8 and PD‐L1, measured by DIA of WSIs and ROIs. We selected 153 primary gastric cancer tissues and stained them with CD8 and PD‐L1. All IHC slides were scanned at ×200 magnification and ratios of CD8 and PD‐L1 were measured in WSIs and ROIs from the invasive front, within the tumor, and the mucosa. Patients with high CD8 and PD‐L1 ratios showed more favorable outcomes compared to those with low ratios. Pathologist‐aided DIA predicted the survival of patients more accurately than WSI analysis (CD8, p = 0.025 versus p = 0.068; PD‐L1, p = 0.008 versus p = 0.2). Although a high density of CD8+ T cells at the invasive front correlated best with patient survival, CD8 ratio in the mucosa could also predict patient outcome. In conclusion, CD8 and PD‐L1 ratios measured by pathologist‐aided DIA predicted survival more accurately than WSI analyses and ROIs at the invasive front correlated best with patient outcome.
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Affiliation(s)
- You Jeong Heo
- The Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Taebum Lee
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Department of Pathology, Chonnam National University Medical School, Hwasun Hospital, Hwasun-gun, Republic of Korea
| | - Sun-Ju Byeon
- Department of Pathology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong-si, Republic of Korea.,Center of Companion Diagnostics, Samsung Medical Center, Seoul, Republic of Korea
| | - Eun Ji Kim
- Center of Companion Diagnostics, Samsung Medical Center, Seoul, Republic of Korea
| | - Hyeong Chan Shin
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Center of Companion Diagnostics, Samsung Medical Center, Seoul, Republic of Korea
| | - Binnari Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Center of Companion Diagnostics, Samsung Medical Center, Seoul, Republic of Korea
| | - So Young Kang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sang Yun Ha
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kyoung-Mee Kim
- The Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Center of Companion Diagnostics, Samsung Medical Center, Seoul, Republic of Korea
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Bansal AK, Sharawat SK, Gupta R, Vishnubhatla S, Dhawan D, Bakhshi S. Regulatory T cells in pediatric AML are associated with disease load and their serial assessment suggests role in leukemogenesis. AMERICAN JOURNAL OF BLOOD RESEARCH 2020; 10:90-96. [PMID: 32923088 PMCID: PMC7486484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 06/23/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND Regulatory T cells (Tregs) modulate immune system by suppressing other immune cells. In current exploratory era of immunotherapy, the detailed enumeration data of Tregs cells in pediatric AML is lacking. AIM Serial assessment of Treg absolute values in pediatric AML at diagnosis and follow-up; and correlating with outcome. STUDY DESIGN Prospective study. METHODS Study objectives were determining Tregs (CD4+CD25+Foxp3+) were assessed at diagnosis, post-induction, post-consolidation, 3 and 6 months follow-up and relapse in 30 consecutive pediatric AML patients. RESULTS Patients with AML had higher baseline Treg frequencies than controls (P=0.0001). Female patients, WBC > 50,000 × 103/L and hypoalbuminemia were significantly associated with high Treg absolute values. Baseline Tregs were not associated with DFS, EFS and OS. Tregs significantly decreased after induction chemotherapy (P=0.028). Using generalized-estimating-equation regression model, Treg absolute numbers continued to decrease at each assessment time point from post-induction till 6 months follow-up (P=0.029) in those who are in continuous CR; however, in those patients who relapsed, Tregs did not change from post-induction till last follow-up preceding relapse (P=0.39). CONCLUSIONS This first study in pediatric AML demonstrates that Tregs are increased at diagnosis; the increased number is significantly associated with female gender and high WBC count. Tregs decrease after induction chemotherapy as compared to their baseline value. Post CR, Treg absolute values continue to decrease significantly in those who stay in CR but not so in those who relapse; this suggests their possible role in leukemogenesis.
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Affiliation(s)
- Anuj Kumar Bansal
- Department of Medical OncologyNew Delhi-110029, India
- Department of Dr. B.R.A. Institute Rotary Cancer HospitalNew Delhi-110029, India
- Department of All India Institute of Medical SciencesNew Delhi-110029, India
| | - Surender Kumar Sharawat
- Department of Medical OncologyNew Delhi-110029, India
- Department of Dr. B.R.A. Institute Rotary Cancer HospitalNew Delhi-110029, India
- Department of All India Institute of Medical SciencesNew Delhi-110029, India
| | - Ritu Gupta
- Department of Laboratory OncologyNew Delhi-110029, India
- Department of Dr. B.R.A. Institute Rotary Cancer HospitalNew Delhi-110029, India
| | - Sreenivas Vishnubhatla
- Department of BiostatisticsNew Delhi-110029, India
- Department of All India Institute of Medical SciencesNew Delhi-110029, India
| | - Deepa Dhawan
- Department of Medical OncologyNew Delhi-110029, India
- Department of Dr. B.R.A. Institute Rotary Cancer HospitalNew Delhi-110029, India
- Department of All India Institute of Medical SciencesNew Delhi-110029, India
| | - Sameer Bakhshi
- Department of Medical OncologyNew Delhi-110029, India
- Department of Dr. B.R.A. Institute Rotary Cancer HospitalNew Delhi-110029, India
- Department of All India Institute of Medical SciencesNew Delhi-110029, India
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High Endothelial Venule with Concomitant High CD8+ Tumor-Infiltrating Lymphocytes Is Associated with a Favorable Prognosis in Resected Gastric Cancer. J Clin Med 2020; 9:jcm9082628. [PMID: 32823631 PMCID: PMC7464373 DOI: 10.3390/jcm9082628] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 08/12/2020] [Accepted: 08/12/2020] [Indexed: 12/24/2022] Open
Abstract
CD8+ tumor-infiltrating lymphocytes (TILs) play a major role in antitumor immunity. High endothelial venules (HEVs) are related to diverse immune cells in solid tumors. We analyzed CD8+ and Foxp3+ TILs in combination with HEVs to determine their prognostic role in advanced gastric cancer (AGC). We enrolled 157 patients with AGC in this study. The densities of CD8+ TILs and Foxp3+ TILs were calculated using immunohistochemical staining. HEVs were evaluated by MECA-79 expression. HEVs were identified in 60 (38.2%) cases and was significantly associated with an increased number of CD8+ TILs (p = 0.027) but not of Foxp3+ TILs (p = 0.455) and CD20+ TILs (p = 0.163). A high CD8+/HEV+ level was significantly associated with nodal metastasis (p = 0.048). In survival analysis, patients with high CD8+/HEV+ levels demonstrated the longest overall survival (OS) (p = 0.015). Furthermore, a high CD8+/HEV+ level was an independent prognostic factor in AGC (p = 0.011; hazard ratio (HR) = 0.435; 95% confidence interval (CI) = 0.245–0.837). HEVs were found to play an important role in antitumor immunity associated with CD8+ TILs in AGC. This analysis of HEVs and CD8+ TILs helps stratify patients with AGC and sheds light on tumor immunity.
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Hashemi V, Maleki LA, Esmaily M, Masjedi A, Ghalamfarsa G, Namdar A, Yousefi M, Yousefi B, Jadidi-Niaragh F. Regulatory T cells in breast cancer as a potent anti-cancer therapeutic target. Int Immunopharmacol 2019; 78:106087. [PMID: 31841758 DOI: 10.1016/j.intimp.2019.106087] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 10/23/2019] [Accepted: 11/25/2019] [Indexed: 02/08/2023]
Abstract
Despite marked advances in treatment approaches, breast cancer is still going to be more prevalent, worldwide. High levels of regulatory T (Treg) cells have repeatedly been demonstrated in circulation, lymph nodes, and tumor samples from patients with various cancer types. The transcription factor Forkhead box protein 3 (Foxp3)-expressing Treg cells have the high suppressive potential of the immune system and are fundamental in preserving immune homeostasis and self-tolerance. However, they enhance tumor development by curbing efficient anti-tumor immune mechanisms in malignancies. Moreover, the accumulation of Treg cells in breast tumors is related to the short overall survival of patients. Treg cell frequency has been applied as an independent predicting factor to diagnose patients with a high risk of relapse. Pulling out all populations of Treg cells to promote the efficacy of anticancer treatment methods may potentially lead to hazardous autoimmune disorders. Thus, realizing the exact structure of tumor-infiltrating Treg cells is pivotal to efficiently target Treg cells in tumors. There are exclusive and non-exclusive approaches to lower down and degrade the number/function of Treg cells. These approaches can include inhibiting tumoral migration, depletion, interference with function, and utilizing T cell plasticity. This review article attempts to clarify the implications concerning the involvement of Treg cells in breast cancer progression and discuss the current approaches in the treatment of this cancer via modulation of Treg cells function.
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Affiliation(s)
- Vida Hashemi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Basic Science, Faculty of Medicine, Maragheh University of Medical Sciences, Maragheh, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Maryam Esmaily
- Department of Medical Entomology and Vector Control, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Masjedi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ghasem Ghalamfarsa
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Afshin Namdar
- Katz Group Centre for Pharmacy and Health Research, University of Alberta, Edmonton, Canada
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahman Yousefi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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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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Zhang N, Cao M, Duan Y, Bai H, Li X, Wang Y. Prognostic role of tumor-infiltrating lymphocytes in gastric cancer: a meta-analysis and experimental validation. Arch Med Sci 2019; 16:1092-1103. [PMID: 32863998 PMCID: PMC7444703 DOI: 10.5114/aoms.2019.86101] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 02/15/2018] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION We performed a meta-analysis and an experimental validation to investigate the association between tumor infiltrating lymphocytes (TILs) and the outcome of gastric cancer (GC) patients to provide prognostic indicators for clinical practice. MATERIAL AND METHODS The relative literature of TILs in tumor tissue from patients with gastric cancer was searched from PubMed, Embase, NIH databases, from April 2000 to 31 December 2016. Studies on the prognostic value of TILs as CD3+, CD4+, CD8+, GrB+, and FOXP3+ lymphocytes for GC were retrieved, and also the related references were traced as supplements. Independent screening documents, extracting information and evaluating quality were implemented independently by 2 evaluators according to the inclusion and exclusion criteria, which were then analyzed by meta-analysis using STATA version 12.0 software. RESULTS The results indicated that high levels of intratumoral CD8+, CD3+ and CD4+ T cell infiltration were associated with better overall survival(OS) in gastric cancer patients, while high density of intratumoral FOXP3+ T cells was not closely associated with a worse outcome. Additionally, in our study, higher density of granzyme B+ (GrB+) T cell infiltration indicated an optimistic prognosis, and infiltration of a larger number of general TILs also suggested a favorable prognosis by log-rank test analysis. CONCLUSIONS This meta-analysis clarified that high levels of CD8+, CD3+, and CD4+ T cell infiltration in tumor tissue showed better OS in GC patients, whereas high density of FOXP3+ T cell infiltration may not be recognized as a negative prognostic factor. These results may provide some useful prognostic indicators for clinical application in gastric cancer.
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Affiliation(s)
- Nana Zhang
- Institute of Cancer Research, School of Basic Medical Science, Xi'an Jiaotong University Xi'an, China
| | - Meng Cao
- Institute of Cancer Research, School of Basic Medical Science, Xi'an Jiaotong University Xi'an, China
| | - Yixin Duan
- Institute of Cancer Research, School of Basic Medical Science, Xi'an Jiaotong University Xi'an, China
| | - Haixia Bai
- Institute of Cancer Research, School of Basic Medical Science, Xi'an Jiaotong University Xi'an, China
| | - Xiang Li
- Institute of Cancer Research, School of Basic Medical Science, Xi'an Jiaotong University Xi'an, China
| | - Yili Wang
- Institute of Cancer Research, School of Basic Medical Science, Xi'an Jiaotong University Xi'an, China
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Recent advances in the study of regulatory T cells in gastric cancer. Int Immunopharmacol 2019; 73:560-567. [PMID: 31181438 DOI: 10.1016/j.intimp.2019.05.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 05/05/2019] [Accepted: 05/06/2019] [Indexed: 12/15/2022]
Abstract
Gastric cancer (GC), which features a complex pathogenesis and mechanism, remains refractory. FOXP3+ regulatory T cells (Tregs), which have been implicated in the progression of gastric cancer, play an immunosuppressive role in the tumor microenvironment. However, the prognostic value of Treg infiltration is still controversial in GC patients. Recently, the association of Tregs with the clinicopathological characteristics of GC patients, the prognostic value of Tregs alone or its combination with other factors to GC patients, the role of Tregs in GC tumor microenvironment, clinical applications and Tregs-targeted therapies for GC patients have become hot issues. In this review, we are going to discuss these scientific researches which focused on these topics.
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13
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Zhang S, Bai W, Tong X, Bu P, Xu J, Xi Y. Correlation between tumor microenvironment-associated factors and the efficacy and prognosis of neoadjuvant therapy for rectal cancer. Oncol Lett 2018; 17:1062-1070. [PMID: 30655866 PMCID: PMC6313063 DOI: 10.3892/ol.2018.9682] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 09/20/2018] [Indexed: 01/20/2023] Open
Abstract
The tumor microenvironment contributes to the survival and development of tumor cells and is therefore a key target for cancer therapy. The tumor microenvironment has unique physical and chemical properties and is associated with inflammation and immunity. To examine the correlation between tumor microenvironment-associated factors and the efficacy and prognosis of neoadjuvant therapy for rectal cancer, and to compare the differences between two treatments [neoadjuvant chemotherapy (NAC) vs. neoadjuvant chemoradiotherapy (NACR)], an immunohistochemical method was used to measure the expression levels of CD4+ tumor-infiltrating lymphocytes (TILs), cluster of differentiation (CD)8+TILs, forkhead box P3 (FOXP3)+TILs, cytotoxic T lymphocyte-associated antigen-4+TILs and programmed death ligand-1 (PD-L1)+TILs in 109 patients with rectal cancer, pre- and post-neoadjuvant therapy. The significance of these protein expression patterns was also analyzed using tissue microarrays, and the prognostic significance of these findings evaluated. The results indicated that high levels of CD4+TILs, CD8+TILs and PD-L1+TILs may be associated with favorable responses to neoadjuvant therapy, whereas high levels of FOXP3+TILs were associated with poor therapeutic responses. Expression levels of CD8+TILs and FOXP3+TILs following neoadjuvant therapy were independent prognostic factors and affected the total survival of patients subjected to neoadjuvant therapy for the treatment of rectal cancer. Moreover, the effects of NAC and NACR on the tumor microenvironment may be different.
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Affiliation(s)
- Siyu Zhang
- Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Wenqi Bai
- Department of Colorectal Surgery, Shanxi Provincial Cancer Hospital, Taiyuan, Shanxi 030013, P.R. China
| | - Xunan Tong
- Departent of Surgery, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Peng Bu
- Department of Pathology, Shanxi Provincial Cancer Hospital, Taiyuan, Shanxi 030013, P.R. China
| | - Jing Xu
- Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Yanfeng Xi
- Department of Pathology, Shanxi Provincial Cancer Hospital, Taiyuan, Shanxi 030013, P.R. China
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14
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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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15
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Lee JS, Won HS, Sun DS, Hong JH, Ko YH. Prognostic role of tumor-infiltrating lymphocytes in gastric cancer: A systematic review and meta-analysis. Medicine (Baltimore) 2018; 97:e11769. [PMID: 30095632 PMCID: PMC6133557 DOI: 10.1097/md.0000000000011769] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 07/11/2018] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND The potential prognostic value of tumor-infiltrating lymphocytes (TILs) in gastric cancer remains controversial. This meta-analysis examines the association between TILs and survival outcomes in gastric cancer. METHODS Twenty-two eligible studies were identified using the PubMed and Google Scholar databases. The combined sample size of the 22 studies was 2941, and the median sample size of the individual studies was 122 patients (52-220). The main clinical outcomes examined were overall cancer survival (OCS) and overall cancer relapse-free survival (OCRFS). RESULTS Tumor tissue CD3(+) TILs, indicative of pan-T-cell expression, had a positive effect on survival with a hazard ratio (HR) of 0.64 (95% confidence interval [CI] 0.52-0.78) for OCS, as did the non-FOXP3(+) T-cell subgroup with an HR of 0.66 (95% CI 0.57-0.75), particularly in CD8(+) lymphocytes (HR = 0.63, 95% CI 0.48-0.83). On the contrary, high FOXP3(+) T-cell expression was correlated with reduced OCS, with an HR of 1.75 (95% CI 1.26-2.42). Analysis of the seven studies evaluating OCRFS revealed improved OCRFS with infiltration of non-FOXP3(+) TILs with an HR of 0.59 (95% CI 0.42-0.81) but not FOXP3(+) T lymphocytes with an HR of 1.82 (95% CI 1.30-2.53). CONCLUSION The results from this meta-analysis suggest that high expression of TILs, mainly by CD8 lymphocytes, may be a potential prognostic biomarker in patients with gastric cancer.
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Affiliation(s)
| | - Hye Sung Won
- Division of Oncology, Department of Internal Medicine
| | - Der Sheng Sun
- Division of Oncology, Department of Internal Medicine
| | - Ji Hyung Hong
- Division of Oncology, Department of Internal Medicine
| | - Yoon Ho Ko
- Division of Oncology, Department of Internal Medicine
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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16
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An Y, Gao S, Zhao WC, Qiu BA, Xia NX, Zhang PJ, Fan ZP. Transforming growth factor-β and peripheral regulatory cells are negatively correlated with the overall survival of hepatocellular carcinoma. World J Gastroenterol 2018; 24:2733-2740. [PMID: 29991878 PMCID: PMC6034152 DOI: 10.3748/wjg.v24.i25.2733] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 04/14/2018] [Accepted: 06/01/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To understand the cellular and molecular changes in peripheral blood that can lead to the development of hepatocellular carcinoma (HCC) and provide new methods for its diagnosis and treatment.
METHODS Peripheral blood mononuclear cells were isolated from the peripheral blood of HCC patients and normal controls and then analyzed by flow cytometry. The percentage of transforming growth factor-β (TGF-β)+ regulatory cells (Tregs) in the peripheral blood was measured, and the expression of TGF-β was also determined. Then, the relationship between the changes and the 5-year survival of patients was analyzed. In addition, recombinant human TGF-β (rhTGF-β) and recombinant human interleukin-6 were added to stimulate the cultured cells, and their effects on HCC were evaluated.
RESULTS The expression of TGF-β and the percentage of TGF-β+ Tregs in the peripheral blood of HCC patients increased significantly compared with normal controls. Compared with the low TGF-β expression group, the high TGF-β expression group had a significantly lower 5-year survival rate, and the same result was found in the two TGF-β+ Treg groups, suggesting that TGF-β and TGF-β+ Tregs were negatively correlated with the overall survival of the patients. In addition, rhTGF-β promoted the growth of tumor cells and induced high expression levels of IL-6, which further promoted tumor proliferation.
CONCLUSION The results showed that TGF-β may promote tumor growth and proliferation by inducing the production of IL-6, and TGF-β and TGF-β+ Tregs may serve as new markers for predicting a poor prognosis in HCC.
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Affiliation(s)
- Yang An
- Department of Hepato-Biliary-Pancreatic Surgery, Navy General Hospital of Chinese People’s Liberation Army, Beijing 100048, China
| | - Song Gao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Wen-Chao Zhao
- Department of Hepato-Biliary-Pancreatic Surgery, Navy General Hospital of Chinese People’s Liberation Army, Beijing 100048, China
| | - Bao-An Qiu
- Department of Hepato-Biliary-Pancreatic Surgery, Navy General Hospital of Chinese People’s Liberation Army, Beijing 100048, China
| | - Nian-Xin Xia
- Department of Hepato-Biliary-Pancreatic Surgery, Navy General Hospital of Chinese People’s Liberation Army, Beijing 100048, China
| | - Peng-Jun Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Zhen-Ping Fan
- Liver Disease Center for Cadre Medical Care, Beijing 302 Military Hospital, Beijing 100039, China
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17
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Yu PC, Long D, Liao CC, Zhang S. Association between density of tumor-infiltrating lymphocytes and prognoses of patients with gastric cancer. Medicine (Baltimore) 2018; 97:e11387. [PMID: 29979429 PMCID: PMC6076141 DOI: 10.1097/md.0000000000011387] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
INTRODUCTION Tumor-infiltrating lymphocytes (TILs) have been shown to be of prognostic significance in patients with gastric cancer. This study aims to investigate the association between density of TILs and prognoses of patients with gastric cancer. METHODS The relative studies of tumor-infiltrating lymphocytes in tumor tissue from patients with gastric cancer were systematically searched from PubMed and Embase until October 31, 2017. The pooled hazard ratios (HRs) and their 95% confidence intervals (95%CI) for overall survival (OS) were estimated. RESULTS Twenty-nine studies involving 4,942 patients were included into analyses. Subset of TILs included CD8, CD3, CD4, and FOXP3 T cell density. Results from meta-analyses revealed that high density of intratumoral CD8 T cells (HR = 0.77, 95% CI 0.63-0.95) and CD3 (HR = 0.62, 95% CI 0.49-0.77) were associated with significantly higher OS than those with low density in patients with gastric cancer. Moreover, a larger number of general TILs density also suggested a favorable prognosis (HR 0.75, 95% CI 0.67-0.84). However, patients with high density of intratumoral FOXP3 T or CD4 T cells were not statistically associated with higher or lower OS than those with low density (HR 1.41, 95% CI 0.97-2.05; HR = 0.86, 95% CI 0.47-1.57). Sample size and follow-up period seemed to influence study outcomes. CONCLUSION The present study revealed that high density of intratumoral CD8 and CD3 T cells were associated with better OS in patients with gastric cancer.
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Affiliation(s)
- Peng-Cheng Yu
- Department of Colorectal Anal Surgery, the First Affiliated Hospital of Guangxi Medical University
| | - Di Long
- Department of Colorectal Anal Surgery, the First Affiliated Hospital of Guangxi Medical University
| | - Cheng-Cheng Liao
- Department of Chemotherapy, the Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Sen Zhang
- Department of Colorectal Anal Surgery, the First Affiliated Hospital of Guangxi Medical University
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18
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Nesseler JP, Schaue D, McBride WH, Nickers P. [Inflammatory and immune biomarkers of radiation response]. Cancer Radiother 2018; 22:180-192. [PMID: 29650389 DOI: 10.1016/j.canrad.2017.09.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 09/08/2017] [Indexed: 02/07/2023]
Abstract
In radiotherapy, the treatment is adapted to each individual to protect healthy tissues but delivers most of time a standard dose according to the tumor histology and site. The only biomarkers studied to individualize the treatment are the HPV status with radiation dose de-escalation strategies, and tumor hypoxia with dose escalation to hypoxic subvolumes using FMISO- or FAZA-PET imaging. In the last decades, evidence has grown about the contribution of the immune system to radiation tumor response. Many preclinical studies have identified some of the mechanisms involved. In this context, we have realised a systematic review to highlight potential inflammatory and immune biomarkers of radiotherapy response. Some are inside the tumor microenvironment, as lymphocyte infiltration or PD-L1 expression, others are circulating biomarkers, including different types of hematological cells, cytokines and chemokines.
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Affiliation(s)
- J P Nesseler
- Department of radiation oncology, David Geffen school of medicine, university of California at Los Angeles, 10833 Le Conte avenue, 90095-1714 Los Angeles, CA, États-Unis.
| | - D Schaue
- Department of radiation oncology, David Geffen school of medicine, university of California at Los Angeles, 10833 Le Conte avenue, 90095-1714 Los Angeles, CA, États-Unis
| | - W H McBride
- Department of radiation oncology, David Geffen school of medicine, university of California at Los Angeles, 10833 Le Conte avenue, 90095-1714 Los Angeles, CA, États-Unis
| | - P Nickers
- Départment de radiothérapie, centre François-Baclesse, rue Émile-Mayrisch, 4240 Esch-sur-Alzette, Luxembourg
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19
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Peng J, Yu Z, Xue L, Wang J, Li J, Liu D, Yang Q, Lin Y. The effect of foxp3-overexpressing Treg cells on non-small cell lung cancer cells. Mol Med Rep 2018; 17:5860-5868. [PMID: 29436663 PMCID: PMC5866031 DOI: 10.3892/mmr.2018.8606] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 12/13/2017] [Indexed: 01/05/2023] Open
Abstract
The aim of the present study was to investigate the novel mechanisms of forkhead box protein P3 (foxp3) in T regulatory (Treg) cells in lung cancer behavior. Treg cells were isolated from the peripheral blood of healthy volunteers and then co-cultured with 95D cells. A plasmid overexpressing foxp3 was constructed and transfected into Treg cells and an MTS assay was performed to assess cell viability. Flow cytometry was performed to evaluate cell apoptosis and reverse transcription-quantitative polymerase chain reaction was used to measure mRNA expression. A Transwell assay was used to assess cell invasion. Treg cells were successfully isolated from peripheral blood with purity of 94.26%. Foxp3 expression in Treg cells was significantly increased following co-culture with 95D cells, while matrix metalloproteinase-9 expression was upregulated in 95D cells co-cultured with Treg cells. The apoptosis, invasion and migration abilities of 95D cells were suppressed by co-culture with Treg cells, whereas the adhesive ability was enhanced. Foxp3 overexpression in Treg cells enhanced the viability and invasiveness of 95D cells, whereas cell adhesion and migration were decreased. The results of the present study demonstrate that the viability and invasiveness of 95D cells are enhanced by foxp3 overexpression in Treg cells, indicating that increased levels of foxp3 in the tumor microenvironment may promote tumor cell growth.
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Affiliation(s)
- Jiangzhou Peng
- Department of Thoracic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510500, P.R. China
| | - Zigang Yu
- Department of Thoracic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510500, P.R. China
| | - Lei Xue
- Department of Thoracic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510500, P.R. China
| | - Jiabin Wang
- Department of Thoracic Surgery, Shanwei People's Hospital, Shanwei, Guangdong 516600, P.R. China
| | - Jun Li
- Department of Thoracic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510500, P.R. China
| | - Degang Liu
- Department of Thoracic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510500, P.R. China
| | - Qiang Yang
- Department of Thoracic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510500, P.R. China
| | - Yihui Lin
- Department of Neurology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510500, P.R. China
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20
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Chaoul N, Tang A, Desrues B, Oberkampf M, Fayolle C, Ladant D, Sainz-Perez A, Leclerc C. Lack of MHC class II molecules favors CD8 + T-cell infiltration into tumors associated with an increased control of tumor growth. Oncoimmunology 2017; 7:e1404213. [PMID: 29399403 PMCID: PMC5790350 DOI: 10.1080/2162402x.2017.1404213] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 11/04/2017] [Accepted: 11/06/2017] [Indexed: 12/22/2022] Open
Abstract
Regulatory T-cells (Tregs) are crucial for the maintenance of immune tolerance and homeostasis as well as for preventing autoimmune diseases, but their impact on the survival of cancer patients remains controversial. In the TC-1 mouse model of human papillomavirus (HPV)-related carcinoma, we have previously demonstrated that the therapeutic efficacy of the CyaA-E7-vaccine, targeting the HPV-E7 antigen, progressively declines with tumor growth, in correlation with increased intratumoral recruitment of Tregs. In the present study, we demonstrated that these TC-1 tumor-infiltrating Tregs were highly activated, with increased expression of immunosuppressive molecules. Both intratumoral effector CD4+ T-cells (Teffs) and Tregs expressed high levels of PD-1, but anti-PD-1 antibody treatment did not impact the growth of the TC-1 tumor nor restore the therapeutic effect of the CyaA-E7 vaccine. To analyze the mechanisms by which Tregs are recruited to the tumor site, we used MHC-II KO mice with drastically reduced numbers of CD4+ effector T-cells. We demonstrated that these mice still had significant numbers of Tregs in their lymphoid organs which were recruited to the tumor. In MHC-II KO mice, the growth of the TC-1 tumor was delayed in correlation with a strong increase in the intratumoral recruitment of CD8+ T-cells. In addition, in mice that spontaneously rejected their tumors, the infiltration of E7-specific CD8+ T-cells was significantly higher than in MHC-II KO mice with a growing tumor. These results demonstrate that tumor-specific CD8+ T-cells can be efficiently activated and recruited in the absence of MHC class II molecules and of CD4+ T-cell help.
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Affiliation(s)
- Nada Chaoul
- Département d'immunologie, Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Equipe Labellisée Ligue Contre le Cancer, France.,Inserm U1041, Paris, France
| | - Alexandre Tang
- Département d'immunologie, Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Equipe Labellisée Ligue Contre le Cancer, France.,Inserm U1041, Paris, France
| | - Belinda Desrues
- Département d'immunologie, Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Equipe Labellisée Ligue Contre le Cancer, France.,Inserm U1041, Paris, France
| | - Marine Oberkampf
- Département d'immunologie, Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Equipe Labellisée Ligue Contre le Cancer, France.,Inserm U1041, Paris, France
| | - Catherine Fayolle
- Département d'immunologie, Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Equipe Labellisée Ligue Contre le Cancer, France.,Inserm U1041, Paris, France
| | - Daniel Ladant
- Département de biologie structurale et de chimie, Institut Pasteur, Unité de Biochimie des Interactions Macromoléculaires, Paris, France.,CNRS, UMR 3528, Paris, France
| | - Alexander Sainz-Perez
- Département d'immunologie, Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Equipe Labellisée Ligue Contre le Cancer, France.,Inserm U1041, Paris, France
| | - Claude Leclerc
- Département d'immunologie, Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Equipe Labellisée Ligue Contre le Cancer, France.,Inserm U1041, Paris, France
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21
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Frydrychowicz M, Boruczkowski M, Kolecka-Bednarczyk A, Dworacki G. The Dual Role of Treg in Cancer. Scand J Immunol 2017; 86:436-443. [PMID: 28941312 DOI: 10.1111/sji.12615] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 09/20/2017] [Indexed: 12/15/2022]
Abstract
Regulatory T cells (Tregs) represent a small subpopulation of CD4+ cells. Tregs are characterized by the expression of transcription factor Forkhead box protein 3 (FoxP3), also known as scurfin. Tregs are modulators of adaptive immune responses and play an important role in maintaining tolerance to self-antigens, providing the suppression associated with tumour microenvironment as well. These immunomodulatory properties are the main reason for the development of numerous therapeutic strategies, designed to inhibit the activity of cancer cells. However, due to Treg subpopulation diversity and its many functional pathways, the role of these cells in the cancer development and progression is still not fully understood.
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Affiliation(s)
- M Frydrychowicz
- Department of Clinical Immunology, Poznan University of Medical Sciences, Poznan, Poland
| | - M Boruczkowski
- Department of Clinical Immunology, Poznan University of Medical Sciences, Poznan, Poland
| | - A Kolecka-Bednarczyk
- Department of Clinical Immunology, Poznan University of Medical Sciences, Poznan, Poland
| | - G Dworacki
- Department of Clinical Immunology, Poznan University of Medical Sciences, Poznan, Poland
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22
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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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23
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Won KY, Kim GY, Kim HK, Choi SI, Kim SH, Bae GE, Lim JU, Lim SJ. Tumoral FOXP3 expression is associated with favorable clinicopathological variables and good prognosis in gastric adenocarcinoma: the tumor suppressor function of tumoral FOXP3 is related with the P21 expression in gastric adenocarcinoma. Hum Pathol 2017; 68:112-118. [PMID: 28882702 DOI: 10.1016/j.humpath.2017.08.023] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2017] [Revised: 08/17/2017] [Accepted: 08/25/2017] [Indexed: 12/15/2022]
Abstract
The function and contribution of tumoral FOXP3 in gastric cancer development remain poorly understood. Thus, we studied the expression of tumoral FOXP3 and its relationship with the well-known tumor suppressor proteins P21 and P53 in gastric adenocarcinoma. The tissue microarray was constructed from 182 cases of gastric adenocarcinoma. The immunohistochemistry was performed on 4-μm tissue sections from each tissue microarray block. We found that positive tumoral FOXP3 expression was significantly correlated with a lower T category, a lower N category, a lower recurrence rate, and less lymphatic invasion. Furthermore, the survival analysis revealed that the tumoral FOXP3-positive group had significantly increased overall survival and disease-free survival rates compared with the tumoral FOXP3-negative group. Additionally, P21 expression showed a significant positive correlation with tumoral FOXP3 expression in gastric adenocarcinoma cells. Taken together, these findings demonstrate that tumoral FOXP3 expression is associated with favorable clinicopathological variables and good prognosis in gastric adenocarcinoma through increased expression of the tumor suppression protein P21.
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Affiliation(s)
- Kyu Yeoun Won
- Department of Pathology, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, 05278, Republic of Korea
| | - Gou Young Kim
- Department of Pathology, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, 05278, Republic of Korea
| | - Hyung Kyung Kim
- Department of Pathology, Graduate School, Kyung Hee University, Seoul, 02453, Republic of Korea
| | - Sung Il Choi
- Department of Surgery, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, 05278, Republic of Korea
| | - Sang Hyun Kim
- Department of Surgery, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, 05278, Republic of Korea
| | - Go Eun Bae
- Department of Pathology, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 21431, Republic of Korea
| | - Jun Uk Lim
- Department of Gastroenterology, Sejong General Hospital, Bucheon, 14754, Republic of Korea
| | - Sung-Jig Lim
- Department of Pathology, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, 05278, Republic of Korea.
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24
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Asghari MH, Moloudizargari M, Ghobadi E, Fallah M, Abdollahi M. Melatonin as a multifunctional anti-cancer molecule: Implications in gastric cancer. Life Sci 2017; 185:38-45. [DOI: 10.1016/j.lfs.2017.07.020] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 07/14/2017] [Accepted: 07/20/2017] [Indexed: 12/13/2022]
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25
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Cho J, Lee J, Bang H, Kim ST, Park SH, An JY, Choi MG, Lee JH, Sohn TS, Bae JM, Kang WK, Kim S, Kim KM. Programmed cell death-ligand 1 expression predicts survival in patients with gastric carcinoma with microsatellite instability. Oncotarget 2017; 8:13320-13328. [PMID: 28076847 PMCID: PMC5355099 DOI: 10.18632/oncotarget.14519] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Accepted: 12/27/2016] [Indexed: 02/06/2023] Open
Abstract
Programmed death-ligand 1 (PD-L1) is expressed in a subgroup of gastric cancers that may benefit from immunotherapy. Microsatellite instability-high (MSI-H) is a potential predictive factor for response to immunotherapy targeting the PD-1 or its ligand PD-L1. The relationship between PD-L1 expression and MSI-H status remains poorly understood. In this study, we investigated PD-L1 expression in patients with MSI-H gastric cancer. We analyzed PD-L1 expression in 78 MSI-H gastric cancer tissue samples using immunohistochemistry. PD-L1 expression was classified as expression on tumor cells or on immune cells. We observed PD-L1 expression in 48 gastric cancer samples (61.5%), consisting of 7 (9.0%) cases with tumor PD-L1 expression and 47 (60.3%) cases with immune cell PD-L1 expression. Immune cell PD-L1 expression was frequently associated with intestinal type cancer by the Lauren classification (p = 0.015), with a lower risk of lymph node metastasis (p = 0.027) and lower tumor stages (p = 0.029) compared to MSI-H gastric cancers without PD-L1 expression. Moreover, immune cell PD-L1 expression was an independent favorable prognostic factor for overall survival (versus PD-L1 negative; hazard ratio, 3.451; 95% confidence interval, 1.172–12.745; p = 0.025). In MSI-H gastric cancer, PD-L1 expression was observed to be independently associated with a longer survival.
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Affiliation(s)
- Junhun Cho
- Department of Pathology, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Jeeyun Lee
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Heejin Bang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung Tae Kim
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Se Hoon Park
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ji Yeong An
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Min Gew Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joon Ho Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Tae Sung Sohn
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae Moon Bae
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Won Ki Kang
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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26
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Park C, Cho J, Lee J, Kang SY, An JY, Choi MG, Lee JH, Sohn TS, Bae JM, Kim S, Kim ST, Park SH, Park JO, Kang WK, Sohn I, Jung SH, Kang MS, Kim KM. Host immune response index in gastric cancer identified by comprehensive analyses of tumor immunity. Oncoimmunology 2017; 6:e1356150. [PMID: 29147610 DOI: 10.1080/2162402x.2017.1356150] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 07/05/2017] [Accepted: 07/07/2017] [Indexed: 12/13/2022] Open
Abstract
Tumor infiltrating lymphocytes (TIL) in Epstein-Barr virus (EBV)-associated/microsatellite-unstable (MSI) gastric carcinomas (GC) constitute immune-active principal cellular components of tumor microenvironment and contribute to better prognosis. With the remarkable success of cancer immunotherapies, there is an urgent need for a comprehensive understanding of tumor-immune interactions in patients with GC in the context of host immune response. To identify GC subtype-specific immune response gene set, we tested differentially expressed genes for MSI and EBV+ GC subtypes in randomly selected test set (n = 278) in merged ACRG-SMC microarray and TCGA RNA sequencing data set. We identified Host ImmunE Response index (HIERÏ) consisting of 29 immune genes classifying GC patients into robust 3 groups with prognostic significance. Immune-high cluster 1 was enriched with PD-L1High/EBV+/MSI/TILHigh with the best clinical outcome while immune-low cluster 3 displayed worst outcome and exemplified with PD-L1Low/EBV-/MSS. The results were validated in the same cohort (n = 279) and independent cohort (n = 181) with RNA from formalin-fixed paraffin-embedded (FFPE) tissue. Unexpectedly, nearly half of GC in cluster 1 were EBV-/MSS and 10% of cluster 3 GC were EBV+/MSI GC patients, suggesting that in addition to EBV+/MSI GC subtypes, EBV-/MSS subtype also constitutes almost half of high immune cluster and would be a good candidate for immune checkpoint inhibitor therapy. In contrary, almost 10% of EBV+/MSI GC patients may not respond to immune checkpoint inhibitor therapy. Thus, our HIERÏ gene signature demonstrates the potential to subclassify tumor immunity levels, predict prognosis and help immunotherapeutic decisions.
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Affiliation(s)
- Charny Park
- Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Clinical Genome Analysis and Precision Medicine Branch, Research Institute, National Cancer Center, Goyang, Republic of Korea
| | - Junhun Cho
- Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Pathology, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - So Young Kang
- Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ji Yeong An
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Min Gew Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jun Ho Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Tae Sung Sohn
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae Moon Bae
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Se Hoon Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joon Oh Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Won Ki Kang
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Insuk Sohn
- Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Seoul, Korea
| | - Sin Ho Jung
- Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Seoul, Korea
| | - Myung-Soo Kang
- Samsung Biomedical Research Institute (SBRI), Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University and Samsung Medical Center, Seoul, Korea.,Lifetech Institute of iNtRON Biotechnology, Seongnam, Korea
| | - Kyoung-Mee Kim
- Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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27
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Kang BW, Kim JG, Lee IH, Bae HI, Seo AN. Clinical significance of tumor-infiltrating lymphocytes for gastric cancer in the era of immunology. World J Gastrointest Oncol 2017; 9:293-299. [PMID: 28808502 PMCID: PMC5534397 DOI: 10.4251/wjgo.v9.i7.293] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 02/02/2017] [Accepted: 06/06/2017] [Indexed: 02/05/2023] Open
Abstract
Immunotherapy has begun to revolutionize cancer treatment, by introducing therapies that target the host immune system instead of the tumor, therapies that possess unique adverse event profiles, and therapies that may cure certain types of cancer. The immune microenvironment of tumors is emerging as the most important means of understanding the relationship between a patient' immune system and their cancer, informing prognosis, and guiding immunotherapy, such as an antibody blockade of immune checkpoints. For some solid tumors, simple quantitation of lymphocyte infiltration would seem to have prognostic significance, suggesting that lymphocyte infiltration is not passive but may actively promote or inhibit tumor growth. For gastric cancers, several studies have provided strong evidence that immune cells contribute to determining prognosis. However, the exact role of immune cells in gastric cancer remains unclear. Therefore, this review focuses on the clinical significance of immune cells, especially tumor-infiltrating lymphocytes, in gastric cancer.
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28
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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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29
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Wessler S, Krisch LM, Elmer DP, Aberger F. From inflammation to gastric cancer - the importance of Hedgehog/GLI signaling in Helicobacter pylori-induced chronic inflammatory and neoplastic diseases. Cell Commun Signal 2017; 15:15. [PMID: 28427431 PMCID: PMC5397778 DOI: 10.1186/s12964-017-0171-4] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 04/07/2017] [Indexed: 02/07/2023] Open
Abstract
Infections with the human pathogen Helicobacter pylori (H. pylori) are closely associated with the development of inflammatory disorders and neoplastic transformation of the gastric epithelium. Drastic changes in the micromilieu involve a complex network of H. pylori-regulated signal transduction pathways leading to the release of proinflammatory cytokines, gut hormones and a wide range of signaling molecules. Besides controlling embryonic development, the Hedgehog/GLI signaling pathway also plays important roles in epithelial proliferation, differentiation, and regeneration of the gastric physiology, but also in the induction and progression of inflammation and neoplastic transformation in H. pylori infections. Here, we summarize recent findings of H. pylori-associated Hedgehog/GLI signaling in gastric homeostasis, malignant development and the modulation of the gastric tumor microenvironment.
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Affiliation(s)
- Silja Wessler
- Division of Microbiology, Cancer Cluster Salzburg, Department of Molecular Biology, Paris-Lodron University of Salzburg, Billroth Strasse 11, A-5020, Salzburg, Austria.
| | - Linda M Krisch
- Division of Microbiology, Cancer Cluster Salzburg, Department of Molecular Biology, Paris-Lodron University of Salzburg, Billroth Strasse 11, A-5020, Salzburg, Austria
| | - Dominik P Elmer
- Division of Molecular Tumor Biology, Cancer Cluster Salzburg, Department of Molecular Biology, Paris-Lodron University of Salzburg, Hellbrunner Strasse 34, A-5020, Salzburg, Austria
| | - Fritz Aberger
- Division of Molecular Tumor Biology, Cancer Cluster Salzburg, Department of Molecular Biology, Paris-Lodron University of Salzburg, Hellbrunner Strasse 34, A-5020, Salzburg, Austria.
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30
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Choi HS, Ha SY, Kim HM, Ahn SM, Kang MS, Kim KM, Choi MG, Lee JH, Sohn TS, Bae JM, Kim S, Kang ES. The prognostic effects of tumor infiltrating regulatory T cells and myeloid derived suppressor cells assessed by multicolor flow cytometry in gastric cancer patients. Oncotarget 2016; 7:7940-51. [PMID: 26799288 PMCID: PMC4884965 DOI: 10.18632/oncotarget.6958] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Accepted: 12/26/2015] [Indexed: 12/23/2022] Open
Abstract
The prognostic effects of tumor infiltrating lymphocytes (TILs), especially regulatory T cells (Tregs) and myeloid derived suppressing cells (MDSCs) are inconclusive in gastric cancers. We investigated the frequencies of TILs including CD8+ T cells, CD45+CD4+CD25± FOXP3+ Tregs, CD45+CD11b+ CD14+ HLA−DR− MDSCs in 28 gastric cancer tissues by using multicolor flow cytometry. In gastric cancer tissue, the percentage of Tregs among the CD4+ T cell subset was substantially increased compared to that of Tregs among peripheral blood CD4+ T cells from the controls. High frequency of CD8+ T cells among CD3+ T cells correlated with increased overall survival (OS) (p = 0.005). High frequency of Tregs among CD4+ T cells correlated with increased OS (p < 0.001), and disease-free survival (DFS) (p = 0.039) and was an independent prognostic factor in OS (Hazard ratio: 0.047; 95% confidence interval, 0.006-0.372; p = 0.004). High frequency of MDSCs among total examined cells correlated with decreased OS (p = 0.027) and was an independent prognostic factor in OS (Hazard ratio 8.601; 95% confidence interval, 1.240-59.678; p = 0.029). We have demonstrated that high levels of Tregs among tumor-infiltrating CD4+ T cells were favorable, but an increased proportion of MDSCs was an adverse independent prognostic factor in gastric cancer. Our results may provide important insights for future immunotherapy in gastric cancer.
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Affiliation(s)
- Han Sol Choi
- Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sang Yun Ha
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hye-Mi Kim
- Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Soo Min Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Myung-Soo Kang
- Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Samsung Biomedical Research Institute (SBRI), Center for Future Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Min Gew Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joon Ho Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Tae Sung Sohn
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae Moon Bae
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Eun-Suk Kang
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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31
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Goode EF, Smyth EC. Immunotherapy for Gastroesophageal Cancer. J Clin Med 2016; 5:jcm5100084. [PMID: 27669318 PMCID: PMC5086586 DOI: 10.3390/jcm5100084] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Revised: 09/07/2016] [Accepted: 09/14/2016] [Indexed: 12/29/2022] Open
Abstract
Survival for patients with advanced oesophageal and stomach cancer is poor; together these cancers are responsible for more than a million deaths per year globally. As chemotherapy and targeted therapies such as trastuzumab and ramucirumab result in modest improvements in survival but not long-term cure for such patients, development of alternative treatment approaches is warranted. Novel immunotherapy drugs such as checkpoint inhibitors have been paradigm changing in melanoma, non-small cell lung cancer and urothelial cancers. In this review, we assess the early evidence for efficacy of immunotherapy in patients with gastroesophageal cancer in addition to considering biomarkers associated with response to these treatments. Early results of Anti- Programmed Cell Death Protein-1 (anti-PD-1), anti-PD-L1 and anti-Cytotoxic T-lymphocyte assosciated protein-4 (anti-CTLA4) trials are examined, and we conclude with a discussion on the future direction for immunotherapy for gastroesophageal cancer patients.
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Affiliation(s)
- Emily F Goode
- The Royal Marsden Hospital, NHS Foundation Trust, London SW3 6JJ, UK.
| | - Elizabeth C Smyth
- The Royal Marsden Hospital, NHS Foundation Trust, London SW3 6JJ, UK.
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32
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Wang J, Yang J. Identification of CD4 +CD25 +CD127 - regulatory T cells and CD14 +HLA -DR -/low myeloid-derived suppressor cells and their roles in the prognosis of breast cancer. Biomed Rep 2016; 5:208-212. [PMID: 27446543 PMCID: PMC4950717 DOI: 10.3892/br.2016.694] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 01/18/2016] [Indexed: 12/12/2022] Open
Abstract
The aim of the present study was to identify cluster of differentiation 4+ (CD4+)CD25+CD127- regulatory T cells (Tregs) and CD14+ human leukocyte antigen-antigen D-related (HLA-DR-)/low myeloid-derived suppressor cells (MDSCs) in patients with breast cancer of varying stages, and investigate their roles and the potential interactions in the prognosis of breast cancer. A total of 40 patients with breast cancer were included in the study. A total of 30 healthy individuals served as the healthy control. Flow cytometry was performed for the identification of biomarkers. Natural Tregs were characterized by the expression of CD4+CD25+CD127-. The MDSC frequency was expressed as the percentage of CD33+CD11b+HLA-DR-lineage markers (Lin)-. The absolute number of Tregs was higher in breast cancer patients compared to the healthy control. The absolute number of Tregs in the patients with stage III or IV breast cancer was higher than those of the stage I or II, respectively. The percentage showed a gradual increase in the patients with breast cancer compared with the normal control. No direct correlation was established between the number or percentage of Tregs and the patient survival. There was a higher percentage of circulating MDSCs in breast cancer patients compared with the normal individuals. A close correlation was established between clinical cancer stage and percentage and total number of circulating MDSCs. To be exact, a significant increase of MDSC percentage and total number was observed in patients with stage III-IV breast cancer compared with the other cancer patients (stage I-II) and the normal individuals. No statistical difference was observed in the 3- and 5-year survival rates in the breast cancer patients with enhanced expression of Tregs, compared with the normal individuals. In conclusion, enhanced expression of CD4+CD25+CD127- Tregs cells and CD33+CD11+HLA-DR-LIN- MDSCs were identified from patients with breast cancer. Patients with advanced stage breast cancer showed upregulation of such cells. However, these 2 types of cells showed no correlation with the prognosis of breast cancer.
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Affiliation(s)
- Jinhu Wang
- Department of Laboratory Medicine, Taicang Affiliated Hospital of Soochow University, Taicang, Jiangsu 215400, P.R. China
| | - Jianhong Yang
- Department of Laboratory Medicine, Taicang Affiliated Hospital of Soochow University, Taicang, Jiangsu 215400, P.R. China
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33
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Guo G, He Z, Shi Z. Correlation between FOXP3 expression and gastric cancer. Oncol Lett 2016; 12:1554-1558. [PMID: 27446470 DOI: 10.3892/ol.2016.4752] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 05/03/2016] [Indexed: 12/21/2022] Open
Abstract
The aim of the present study was to investigate the expression and function of forkhead box protein 3 (FOXP3) in gastric cancer using a rat model. A total of 92 Wistar rats were divided into two groups: An experimental group (n=46) and a control group (n=46). In the experimental group, sarcosine ethyl ester hydrochloride and sodium nitrite carcinogens were administered for 6 months to induce gastric cancer, whereas the control group was administered saline. Reverse transcription-polymerase chain reaction, immunoblotting, immunohistochemistry and western blotting were applied to analyze FOXP3 expression in gastric cancer and normal gastric tissue in the experimental and control groups, respectively. The association between FOXP3 expression and gastric cancer pathogenesis was investigated. In the experimental group, 6/46 rats developed hyperplastic lesions (grade I), 8 rats developed precancerous lesions (grade II), 18 rats developed early stage gastric cancer (grade III) and 14 rats developed gastrointestinal invasive carcinoma (grade IV). FOXP3 transcription and expression was observed in all gastric tissues of the experimental group. FOXP3 transcription and expression levels were significantly higher in the experimental group than in the control group (P<0.05). Furthermore, in the experimental group, a higher lesion grade was associated with a higher level of FOXP3 transcription and expression (P<0.05). FOXP3 protein was predominantly distributed in the tumor nuclei of the gastric cancer tissues. In the 32 pathological slices of gastric cancer tissue obtained from the experimental group, 20 cases (62.50%) exhibited positive FOXP3 staining. In the hyperplastic (grade I) and precancerous gastric (grade II) tissues, 2 cases (33.33%) and 4 cases (50.00%) exhibited positive FOXP3 staining, respectively. However, no positive FOXP3 expression was identified in the 46 pathological gastric tissue slices obtained from the control group. In conclusion, the expression of FOXP3 exhibits a positive correlation with gastric lesion grade. Therefore, FOXP3 may exhibit an important function in the occurrence and development of gastric cancer.
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Affiliation(s)
- Guoxiao Guo
- Department of General Surgery, Henan University Huaihe Hospital, Kaifeng, Henan 475000, P.R. China
| | - Zhikuan He
- Department of General Surgery, Henan University Huaihe Hospital, Kaifeng, Henan 475000, P.R. China
| | - Zhaohui Shi
- Department of General Surgery, Henan University Huaihe Hospital, Kaifeng, Henan 475000, P.R. China
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Role of Regulatory T-cells in Different Clinical Expressions of Helicobacter pylori Infection. Arch Med Res 2016; 47:245-54. [DOI: 10.1016/j.arcmed.2016.07.013] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 07/22/2016] [Indexed: 12/15/2022]
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Chen X, Du Y, Lin X, Qian Y, Zhou T, Huang Z. CD4+CD25+ regulatory T cells in tumor immunity. Int Immunopharmacol 2016; 34:244-249. [PMID: 26994448 DOI: 10.1016/j.intimp.2016.03.009] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 02/22/2016] [Accepted: 03/08/2016] [Indexed: 01/11/2023]
Abstract
Regulatory T cells (Tregs) are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases. Depletion of Tregs results in the onset of a variety of autoimmune diseases. Tregs are defined based on expression of CD4, CD25, and the transcription factor, FoxP3. It is now clear that three inhibitory cytokines, IL-10, IL-35 and TGF-β, are key mediators of Tregs function. Tregs have been shown to be important contributors to the development of immune tolerance toward tumors and play a critical role in the induction of tolerance to tumor associated antigens and suppression of anti-tumor immunity. Increasing researches support the existence of elevated numbers of regulatory T cells in cancer patients. Poor prognosis and decreased survival rates are closely correlated with higher Treg cell frequencies. Depletion of Tregs or blockade of their immune inhibitory role can enhance anti-tumor effects. Recent evidence suggests that Tregs may be responsible for the failure of host anti-tumor immunity by suppressing cytotoxic T-cells. In this review, we discuss cellular and molecular mechanisms in the differentiation and function of Tregs in tumor immunity.
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Affiliation(s)
- Xin Chen
- Department of Gastroenterology and Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Yong Du
- Department of Pediatrics, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - XiuQing Lin
- Department of Gastroenterology and Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Yan Qian
- Department of Pediatrics, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Ting Zhou
- Department of Pediatrics, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - ZhiMing Huang
- Department of Gastroenterology and Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China.
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Dirican N, Karakaya YA, Gunes S, Daloglu FT, Dirican A. Association of intra-tumoral tumour-infiltrating lymphocytes and neutrophil-to-lymphocyte ratio is an independent prognostic factor in non-small cell lung cancer. CLINICAL RESPIRATORY JOURNAL 2015; 11:789-796. [PMID: 26619201 DOI: 10.1111/crj.12417] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2015] [Accepted: 11/13/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Studies suggest that tumour-infiltrating lymphocytes (TILs) and inflammation markers have independent roles in non-small cell lung cancer (NSCLC), but the relationship between the two pronostic factors remains unclear. In this study, we investigated TILs and inflammation markers in with patients advanced stage NSCLC and assessed the association of their levels with prognosis. MATERIALS AND METHODS TILs were evaluated by immunohistochemical staining for cluster of differentiation 3 (CD3) and cluster of differentiation 5 (CD5) and by hematoxylin and eosin staining for non-specific lymphocyte. We investigated the localisation pattern of TILs in advanced stage NSCLC. We divided all cases into two groups: TILs-high and TILs-low groups, by 75th percentile of the population of. In our study, inflammation markers were assessed by C-reactive protein (CRP) and the neutrophil-to-lymphocyte ratio (NLR). RESULTS The results showed that the presence of intra-tumoral high CD3+ and low CD5+ were an independent prognostic factor for overall survival (respectively, P = 0.022 and P = 0.025). Moreover, the high NLR and serum high CRP levels were associated with poor survival (respectively, P = 0.008; P = 0.027). In multi-variate survival analysis, the high CD3+ , low CD5+ , high NLR, tumour node metastasis (TNM) stage, depth of tumour invasion and lymph node metastasis remained independent prognostic factors (respectively, P = 0.018, P = 0.020, P = 0.024, P = 0.038, P = 0.020 and P = 0.047).The high NLR was detected negative correlation with intra-tumoral CD3+ and positive correlation with intra-tumoral CD5+ (respectively, r = -0.623, P = 0.012; r = 0.628, P = 0.028). CONCLUSIONS This study is first report demonstrating the prognostic value of intra-tumoral low CD5+ with NSCLC. Increased CD3+ and low CD5+ was observed in patients with poor prognosis; the two molecules were correlated with NLR, suggesting that inflammation might be used as improve therapeutic efficacy to immunotherapy for advanced NSCLC.
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Affiliation(s)
- Nigar Dirican
- Department of Chest Diseases, Suleyman Demirel University of Medicine, Isparta, Turkey
| | | | - Sedat Gunes
- Department of Thoracic Surgery, Isparta State Hospital, Isparta, Turkey
| | | | - Ahmet Dirican
- Department of Medical Oncology, Celal Bayar University Faculty of Medicine, Manisa, Turkey
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Suh JH, Won KY, Kim GY, Bae GE, Lim SJ, Sung JY, Park YK, Kim YW, Lee J. Expression of tumoral FOXP3 in gastric adenocarcinoma is associated with favorable clinicopathological variables and related with Hippo pathway. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:14608-14618. [PMID: 26823784 PMCID: PMC4713570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Accepted: 10/22/2015] [Indexed: 06/05/2023]
Abstract
FOXP3 is a transcription factor and well-known hallmark of immune suppressive T regulatory cells (Tregs). Recent studies indicate that, in addition to its association with Treg function in the immune system, FOXP3 plays an important role in tumor development. And important tumor suppressor relay between the FOXP3 and Hippo pathways was found in human cancer. Thus, we investigated tumoral FOXP3, infiltrated Tregs count, Lats2, and YAP expression in gastric adenocarcinoma, and the relationships between expression of these three proteins and p53, Ki67, and other clinicopathological variables. We used 118 gastric adenocarcinoma tissues via immunohistochemical analysis, using a tissue microarray, in relation to survival and other clinicopathological factors. We report the several novel observations about the relationship between tumoral FOXP3 and Hippo pathway components in gastric adenocarcinoma. Positive tumoral FOXP3 expression was significantly related with smaller tumor size, tubular tumor type, lower histological grade, lower T stage, lower recurrence rate, less lymphatic invasion, and less neural invasion. Furthermore, patients with positive tumoral FOXP3 experienced significantly better disease-free and overall survival compared to patients with negative tumoral FOXP3. These findings show that tumoral FOXP3 expression is associated with favorable clinicopathological variables in gastric adenocarcinoma. And we report the novel observation of a relationship between tumoral FOXP3 and Hippo pathway components in gastric adenocarcinoma. Tumoral FOXP3 expression, infiltrated Tregs count, and Lats2 expression were all positively correlated with YAP expression. These findings suggest that the Hippo pathway in gastric adenocarcinoma might be influenced by both tumoral FOXP3 and infiltrated Tregs. In conclusion, the loss of FOXP3 expression in cancer cells is thought to contribute to tumorigenesis and progression of gastric adenocarcinoma. The expression of FOXP3 in gastric adenocarcinoma is related with Lats2 and YAP expression of the Hippo pathway.
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Affiliation(s)
- Jung-Ho Suh
- Department of Internal Medicine, Graduate School of Medicine, Kyung Hee UniversitySeoul, South Korea
| | - Kyu Yeoun Won
- Department of Pathology, Kyung Hee University Hospital at Gangdong, School of Medicine, Kyung Hee UniversitySeoul, South Korea
| | - Gou Young Kim
- Department of Pathology, Kyung Hee University Hospital at Gangdong, School of Medicine, Kyung Hee UniversitySeoul, South Korea
| | - Go Eun Bae
- Department of Pathology, Kyung Hee University Hospital at Gangdong, School of Medicine, Kyung Hee UniversitySeoul, South Korea
| | - Sung-Jig Lim
- Department of Pathology, Kyung Hee University Hospital at Gangdong, School of Medicine, Kyung Hee UniversitySeoul, South Korea
| | - Ji-Youn Sung
- Department of Pathology, Kyung Hee University Hospital, School of Medicine, Kyung Hee UniversitySeoul, South Korea
| | - Yong-Koo Park
- Department of Pathology, Kyung Hee University Hospital, School of Medicine, Kyung Hee UniversitySeoul, South Korea
| | - Youn Wha Kim
- Department of Pathology, Kyung Hee University Hospital, School of Medicine, Kyung Hee UniversitySeoul, South Korea
| | - Juhie Lee
- Department of Pathology, Kyung Hee University Hospital, School of Medicine, Kyung Hee UniversitySeoul, South Korea
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Wu MH, Lee WJ, Hua KT, Kuo ML, Lin MT. Macrophage Infiltration Induces Gastric Cancer Invasiveness by Activating the β-Catenin Pathway. PLoS One 2015; 10:e0134122. [PMID: 26226629 PMCID: PMC4520459 DOI: 10.1371/journal.pone.0134122] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 07/06/2015] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Despite evidence that activated macrophages act in an inflammatory microenvironment to promote gastric tumorigenesis via β-catenin signaling, the effects of β-catenin signaling on gastric cancer cell metastasis and the relationship of these cells with surrounding tumor associated macrophages have not been directly studied. METHODS Immunohistochemical staining was employed to analyze 103 patients. An invasion assay was used to evaluate the relationship between macrophages and gastric cancer cells. β-catenin gain-of-function and loss-of-function approaches were performed. To assess the β-catenin regulation mechanism in gastric cancer cells, Western blotting and reverse-transcription polymerase chain reaction were used. RESULTS Increased density of macrophages was associated with advanced stage and poor survival. Gastric cancer cell lines co-cultured with macrophages conditioned medium showed increased nuclear accumulation of β-catenin and increased invading ability. AKT but not ERK regulated β-catenin translocation. MMP7 and CD44, both β-catenin downstream genes, were involved in macrophage-activated gastric cancer cell invasion. CONCLUSION(S) Collectively, the clinical data suggest that macrophage infiltration is correlated with increased grade and poor prognosis for gastric cancer patients who underwent radical resection. Macrophages may induce invasiveness by activating the β-catenin pathway.
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Affiliation(s)
- Ming-Hsun Wu
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Wei-Jiunn Lee
- Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Kuo-Tai Hua
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Min-Liang Kuo
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ming-Tsan Lin
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medical Education & Bioethics, Graduate Institute of Medical Education & Bioethics, National Taiwan University College of Medicine, Taiwan
- * E-mail:
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Gerber AL, Münst A, Schlapbach C, Shafighi M, Kiermeir D, Hüsler R, Hunger RE. High expression of FOXP3 in primary melanoma is associated with tumour progression. Br J Dermatol 2015; 170:103-9. [PMID: 24116716 DOI: 10.1111/bjd.12641] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/15/2013] [Indexed: 12/27/2022]
Abstract
BACKGROUND The antitumour immune response plays an important role in the prognosis of melanoma. High numbers of circulating regulatory T cells have been associated with rapid disease progression. OBJECTIVES To assess the influence of forkhead box protein (FOXP)3, CD1a and langerin expression on the prognosis of primary melanoma. METHODS We analysed 185 primary melanomas by immunohistochemical staining for expression of the regulatory T-cell marker FOXP3 and the dendritic cell markers langerin and CD1a, and correlated marker expression with clinical outcome. RESULTS Disease-free survival and overall survival were significantly longer in patients expressing low levels of FOXP3 in the primary melanoma, whereas they were associated with high expression of CD1a. The negative prognostic value of FOXP3 expression was independent of the Breslow tumour thickness. Langerin expression did not correlate with the clinical outcome. CONCLUSIONS High expression of FOXP3 in the primary melanoma may be used as an additional independent prognostic marker for early tumour progression in patients with melanoma.
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Affiliation(s)
- A L Gerber
- Department of Dermatology, Inselspital, University Hospital Bern, Bern, Switzerland
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Marabelle A, Kohrt H, Caux C, Levy R. Intratumoral immunization: a new paradigm for cancer therapy. Clin Cancer Res 2014; 20:1747-56. [PMID: 24691639 DOI: 10.1158/1078-0432.ccr-13-2116] [Citation(s) in RCA: 183] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Immune cell infiltration in the tumor microenvironment is of prognostic and therapeutic import. These immune cell subsets can be heterogeneous and are composed of mature antigen-presenting cells, helper and effector cytotoxic T cells, toleragenic dendritic cells, tumor-associated macrophages, and regulatory T cells, among other cell types. With the development of novel drugs that target the immune system rather than the cancer cells, the tumor immune microenvironment is not only prognostic for overall patient outcome, but also predictive for likelihood of response to these immune-targeted therapies. Such therapies aim to reverse the cancer immunotolerance and trigger an effective antitumor immune response. Two major families of immunostimulatory drugs are currently in clinical development: pattern recognition receptor agonists (PRRago) and immunostimulatory monoclonal antibodies (ISmAb). Despite their immune-targeted design, these agents have so far been developed clinically as if they were typical anticancer drugs. Here, we review the limitations of this conventional approach, specifically addressing the shortcomings of the usual schedules of intravenous infusions every 2 or 3 weeks. If the new modalities of immunotherapy target specific immune cells within the tumor microenvironment, it might be preferable to deliver them locally into the tumor rather than systemically. There is preclinical and clinical evidence that a therapeutic systemic antitumor immune response can be generated upon intratumoral immunomodulation. Moreover, preclinical results have shown that therapeutic synergy can be obtained by combining PRRagos and ISmAbs to the local tumor site.
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Affiliation(s)
- Aurélien Marabelle
- Authors' Affiliations: Centre de Recherche en Cancérologie de Lyon, UMR INSERM U1052 CNRS 5286, Centre Léon Bérard, Université de Lyon, Lyon, France; and Division of Oncology, Stanford University, Department of Medicine, Stanford, California
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Sherston SN, Vogt K, Schlickeiser S, Sawitzki B, Harden PN, Wood KJ. Demethylation of the TSDR is a marker of squamous cell carcinoma in transplant recipients. Am J Transplant 2014; 14:2617-22. [PMID: 25250867 PMCID: PMC4497351 DOI: 10.1111/ajt.12899] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Revised: 06/19/2014] [Accepted: 06/20/2014] [Indexed: 01/25/2023]
Abstract
Malignancy is an important cause of death in transplant recipients. Cutaneous squamous cell carcinoma (cSCC) causes significant morbidity and mortality as 30% of transplant recipients will develop cSCC within 10 years of transplantation. Previously we have shown that high numbers of regulatory T cells (Tregs) are associated with the development of cSCC in kidney transplant recipients (KTRs). Demethylation analysis of the Treg-specific demethylated region (TSDR) provides a more accurate association with cSCC risk after transplantation. Age, gender and duration of immunosuppression matched KTRs with (n=32) and without (n=27) cSCC, were re-analyzed for putative clinical and immunological markers of cancer risk. The proportion of FOXP3+ CD4+ cells was higher in the population with a previous SCC. Major T cell subsets remained stable over time; although B cell, CD8 and CD4 subpopulations demonstrated age-related changes. TSDR methylation analysis allowed clarification of Treg numbers, enhancing the association of high Treg levels in KTRs with cSCC compared to the cSCC-free cohort. These data validate and expand on previous findings in long-term KTRs, and show that immune markers remain stable over time. TSDR demethylation analysis provides a more accurate biomarker of cancer posttransplantation.
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Affiliation(s)
- S N Sherston
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of OxfordOxford, United Kingdom
| | - K Vogt
- Institute for Medical Immunology, Charité–University MedicineBerlin, Germany
| | - S Schlickeiser
- Institute for Medical Immunology, Charité–University MedicineBerlin, Germany
| | - B Sawitzki
- Institute for Medical Immunology, Charité–University MedicineBerlin, Germany,BCRT Berlin Brandenburg Center for Regenerative Therapies, Charite University MedicineBerlin, Germany
| | - P N Harden
- Oxford Transplant Centre, Churchill HospitalOxford, United Kingdom
| | - K J Wood
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of OxfordOxford, United Kingdom,*Corresponding author: Kathryn J. Wood,
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Li L, Yang C, Zhao Z, Xu B, Zheng M, Zhang C, Min Z, Guo J, Rong R. Skewed T-helper (Th)1/2- and Th17/T regulatory‑cell balances in patients with renal cell carcinoma. Mol Med Rep 2014; 11:947-53. [PMID: 25352158 PMCID: PMC4262517 DOI: 10.3892/mmr.2014.2778] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Accepted: 09/24/2014] [Indexed: 12/21/2022] Open
Abstract
The characterization of CD4+ T-cell subsets reflects the immune status and is important in the maintenance of tumorigenesis and homeostasis. To identify changes in the balance of T helper (Th)1, Th2, Th17 and regulatory T cells (Treg) in individuals with renal cell carcinoma (RCC), the present study investigated a total of 131 patients with RCC and 36 healthy volunteers. The number of CD4+ T-bet+ cells, CD4+ GATA binding protein 3+ cells, CD4+ RAR-related orphan receptor γt+ cells, CD4+ CD25hi CD127lo CD45RA− cells and CD4+ CD25hi CD127lo CD45RA+ cells, defined as Th1, Th2, Th17, activated and naïve Treg cells, respectively, were detected in the peripheral blood using flow cytometric analysis. In addition, tumor-infiltrating forkhead box P3 (Foxp3)+ cells were examined using immunohistochemistry. Compared with healthy volunteers, a significant decrease in the peripheral percentages of Th1, activated and naïve Treg cells was observed in patients with RCC, while those of the Th2 and Th17 cells were increased. In particular, as the tumor stage and grade progressed, the levels of Th1, activated and naïve Treg cells in the peripheral blood decreased; however, the levels of Th2 and Th17 cells increased. Furthermore, the number of tumor-infiltrating Foxp3+ cells increased with increasing tumor stage. These results demonstrated that the balance of Th1 and Th2 cells was skewed towards the Th2 profile and the balance of Th17 and Treg cells was skewed towards the Th17 profile in the peripheral blood of patients with renal cell carcinoma (RCC) and Treg cells were recruited to the tumor sites. Therefore, dysfunctional host anti-tumor immunity was observed in patients with RCC, with a skewed Th1/Th2 and Th17/Treg balance.
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Affiliation(s)
- Long Li
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Cheng Yang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Zitong Zhao
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Bin Xu
- Department of Transfusion, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Minghuan Zheng
- Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Chao Zhang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Zhihui Min
- Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Jianming Guo
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Ruiming Rong
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
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Huang Y, Liao H, Zhang Y, Yuan R, Wang F, Gao Y, Wang P, Du Z. Prognostic value of tumor-infiltrating FoxP3+ T cells in gastrointestinal cancers: a meta analysis. PLoS One 2014; 9:e94376. [PMID: 24827118 PMCID: PMC4020764 DOI: 10.1371/journal.pone.0094376] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Accepted: 03/15/2014] [Indexed: 12/18/2022] Open
Abstract
PURPOSE Tumor-infiltrating FoxP3+ T cells have been reported in various human tumors, which impaired cell-mediated immunity and promoted disease progression. However, its prognostic value for survival in patients with different gastrointestinal cancers [hepatocellular carcinoma (HCC), colorectal cancer (CRC), gastric cancer (GC)] remains controversial. METHODS Relevant literature was searched using PubMed, Embase, Cochrane, Ovid Medline and Chinese wanfang databases. A meta-analysis was conducted to estimate pooled survival and recurrence ratios. The odds ratio (OR) and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials. RESULTS For HCC and GC, the overall survival at 1, 3 and 5-year of high FoxP3+ T cells infiltration patients were lower than low FoxP3+ T cells infiltration patients (P<0.05). The recurrences at 1, 3 and 5-year of high FoxP3+ T cells infiltration patients were higher than low FoxP3+ T cells infiltration patients (P<0.001). But for CRC, the overall survival at 1, 3 and 5-year of high FoxP3+ T cells infiltration patients were higher than low FoxP3+ T cells infiltration patients (P<0.001). There were no differences in 1, 3 and 5-year recurrences between high and low FoxP3+ T cells infiltration patients (P>0.05). CONCLUSIONS Our findings suggested that tumor-infiltrating FoxP3+ T cells were a factor for a poor prognosis for HCC and GC, but a good prognosis for CRC.
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MESH Headings
- Carcinoma, Hepatocellular/diagnosis
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/pathology
- Colorectal Neoplasms/diagnosis
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/mortality
- Colorectal Neoplasms/pathology
- Female
- Forkhead Transcription Factors/genetics
- Forkhead Transcription Factors/metabolism
- Gene Expression
- Humans
- Liver Neoplasms/diagnosis
- Liver Neoplasms/genetics
- Liver Neoplasms/mortality
- Liver Neoplasms/pathology
- Lymphocytes, Tumor-Infiltrating/metabolism
- Lymphocytes, Tumor-Infiltrating/pathology
- Male
- Neoplasm Recurrence, Local/diagnosis
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/mortality
- Neoplasm Recurrence, Local/pathology
- Odds Ratio
- Prognosis
- Stomach Neoplasms/diagnosis
- Stomach Neoplasms/genetics
- Stomach Neoplasms/mortality
- Stomach Neoplasms/pathology
- Survival Analysis
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Affiliation(s)
- Yong Huang
- Tianjin Medical University, Tianjin, China
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Huaiwei Liao
- Department of plastic surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yong Zhang
- Tianjin Medical University, Tianjin, China
| | - Rongfa Yuan
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Fengmei Wang
- Department of Gastroenterology and Hepatology, The Third Central Hospital of Tianjin, Tianjin, China
| | - Yingtang Gao
- Key Laboratory of Artificial Cell, Institute of Hepatobiliary Disease, The Third Central Hospital of Tianjin, Tianjin, China
| | - Peng Wang
- Key Laboratory of Artificial Cell, Institute of Hepatobiliary Disease, The Third Central Hospital of Tianjin, Tianjin, China
| | - Zhi Du
- Key Laboratory of Artificial Cell, Institute of Hepatobiliary Disease, The Third Central Hospital of Tianjin, Tianjin, China
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Szylberg Ł, Bodnar M, Harasymczuk J, Marszalek A. Expression of FoxP3 protein plays a key role in thyroid tumors in children. Fetal Pediatr Pathol 2014; 33:84-91. [PMID: 24328999 DOI: 10.3109/15513815.2013.864347] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
The expression of FoxP3 in tumor cells might play an important role in cancer progression. We evaluated the immunoexpression of FoxP3 in thyroid tumors in children. Studies revealed high nuclear FoxP3 expression in follicular adenoma, papillary carcinoma, follicular carcinoma and low in goiter. Malignant tumors and adenomas, revealed a statistically significant higher expression of FoxP3 compared with the thyroid goiter. High FoxP3 expression in malignant lesions compared with low expression in goiter, may be indirect evidence of its role in carcinogenesis. Revealed high expression of FoxP3 in benign tumor, may suggest a strong activation of oncogenic processes in this lesion.
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Affiliation(s)
- Łukasz Szylberg
- 1 Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Torun, Bydgoszcz, Poland
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Hou J, Yu Z, Xiang R, Li C, Wang L, Chen S, Li Q, Chen M, Wang L. Correlation between infiltration of FOXP3+ regulatory T cells and expression of B7-H1 in the tumor tissues of gastric cancer. Exp Mol Pathol 2014; 96:284-91. [PMID: 24657498 DOI: 10.1016/j.yexmp.2014.03.005] [Citation(s) in RCA: 115] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 01/28/2014] [Accepted: 03/13/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND Substantial evidence suggests that the expansion of regulatory T cells (T(regs)) plays a pivotal role in immunological evasion of tumors. Recent studies have demonstrated that a majority of tumor cells overexpress B7-H1, and this overexpression is associated with poor disease prognosis. Although an increase of T(regs) and B7-H1 has been revealed in several malignancies, their correlation in gastric cancer has not been studied. METHODS Tumor sections from 111 gastric cancer patients were stained for FOXP3 and B7-H1 by immunohistochemistry. The expression levels of these two molecules were statistically associated with various factors involved in disease progression and prognosis. The correlation between their expression levels was analyzed. RESULTS The infiltration of FOXP3(+) T(regs) and expression of B7-H1 were observed in gastric cancer tissues, and there was a highly significant correlation between these two molecules (P < 0.01). The expression of FOXP3(+) T(regs) and B7-H1 was associated with lymph node metastasis and the clinicopathological stage and prognosis of gastric cancer patients. The expression levels of these two determinants in patients with lymph node metastasis and an advanced clinicopathological stage were distinctly higher (P < 0.05). The patients with enhanced expression of FOXP3(+) T(regs) and B7-H1 exhibited a lower overall survival rate and a worse prognosis (P < 0.05). CONCLUSIONS Increased expression of FOXP3(+) T(regs) and B7-H1 was observed in gastric cancer tissues; the two molecules were closely correlated with each other, suggesting that they might be used as new biomarkers to predict the disease progression and prognosis. Combinatorial immunotherapeutic approaches based on depleting the T(regs) and blocking B7-H1 might improve therapeutic efficacy in gastric cancer.
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Affiliation(s)
- Jingying Hou
- The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiangxi Road, Guangzhou, Guangdong, China
| | - Zhong Yu
- The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiangxi Road, Guangzhou, Guangdong, China
| | - Rengyun Xiang
- The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiangxi Road, Guangzhou, Guangdong, China
| | - Chuqiang Li
- The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiangxi Road, Guangzhou, Guangdong, China
| | - Lin Wang
- The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiangxi Road, Guangzhou, Guangdong, China
| | - Shufen Chen
- The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiangxi Road, Guangzhou, Guangdong, China
| | - Qingyun Li
- The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiangxi Road, Guangzhou, Guangdong, China
| | - Mei Chen
- The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiangxi Road, Guangzhou, Guangdong, China
| | - Linyun Wang
- The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiangxi Road, Guangzhou, Guangdong, China.
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Kim S, Lee A, Lim W, Park S, Cho MS, Koo H, Moon BI, Sung SH. Zonal difference and prognostic significance of foxp3 regulatory T cell infiltration in breast cancer. J Breast Cancer 2014; 17:8-17. [PMID: 24744792 PMCID: PMC3988347 DOI: 10.4048/jbc.2014.17.1.8] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Accepted: 03/08/2014] [Indexed: 02/06/2023] Open
Abstract
PURPOSE Forkhead box P3 (Foxp3) is known as the most specific marker for regulatory T lymphocytes, which play an important role in immune tolerance to disturb antitumor immunity. The present study aimed to investigate the prognostic significance of Foxp3 regulatory T lymphocyte (Foxp3 Treg) infiltration in breast cancer. METHODS Immunohistochemical studies with Foxp3, CD4, and CD8 were performed on representative full tissue sections from 143 patients with invasive ductal carcinoma, not otherwise specified. Foxp3 Treg infiltration and the ratios between Foxp3 Treg and CD4 or CD8 T cells were separately analyzed for the tumor bed and tumor periphery to evaluate their association with different clinicopathological parameters and patients' outcome. RESULTS The tumor periphery was considerably more densely infiltrated by Foxp3 Treg, CD4, and CD8 T cells than the tumor bed. Unfavorable clinicopathological parameters (a Ki-67 labeling index of ≥14%, a worse histologic grade, a worse nuclear grade, hormone receptor negativity, human epidermal growth factor receptor 2 positivity, and tumor recurrence) were associated with increased Foxp3 Treg infiltration and a high ratio between Foxp3 Treg and CD4/CD8 T cells. In the tumor periphery, as Foxp3 Treg infiltration and the Foxp3 Treg/CD8 ratio increased, patients' 5-year disease-free survival rate decreased. CONCLUSION The infiltration densities of Foxp3 Treg, CD4, and CD8 T cells were markedly different between the tumor bed and periphery. Besides the absolute count of Foxp3 Treg, the ratio between Foxp3 Treg and effector T cells was a significant prognostic factor in breast cancer.
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Affiliation(s)
- Sewha Kim
- Department of Pathology, Ewha Womans University School of Medicine, Seoul, Korea
| | - Anbok Lee
- Department of Surgery, Ewha Womans University School of Medicine, Seoul, Korea
| | - Woosung Lim
- Department of Surgery, Ewha Womans University School of Medicine, Seoul, Korea
| | - Sanghui Park
- Department of Pathology, Ewha Womans University School of Medicine, Seoul, Korea
| | - Min Sun Cho
- Department of Pathology, Ewha Womans University School of Medicine, Seoul, Korea
| | - Heasoo Koo
- Department of Pathology, Ewha Womans University School of Medicine, Seoul, Korea
| | - Byung-In Moon
- Department of Surgery, Ewha Womans University School of Medicine, Seoul, Korea
| | - Sun Hee Sung
- Department of Pathology, Ewha Womans University School of Medicine, Seoul, Korea
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Rahimian G, Sanei MH, Shirzad H, Azadegan-Dehkordi F, Taghikhani A, Salimzadeh L, Hashemzadeh-Chaleshtori M, Rafieian-Kopaei M, Bagheri N. Virulence factors of Helicobacter pylori vacA increase markedly gastric mucosal TGF-β1 mRNA expression in gastritis patients. Microb Pathog 2014; 67-68:1-7. [PMID: 24462401 DOI: 10.1016/j.micpath.2013.12.006] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2013] [Revised: 12/14/2013] [Accepted: 12/30/2013] [Indexed: 12/23/2022]
Abstract
OBJECTIVE Helicobacter pylori (H. pylori) infection is the main cause of gastric inflammation. Regulatory T cells (Treg cells) suppress the activation and proliferation of antigen-specific T cells and mediate immunologic tolerance. TGF-β1 was shown to be secreted in a subset of Treg cells known as 'Th3 cells'. These cells have not been sufficiently studied in context to H. pylori-induced inflammation in human gastric mucosa. In this study we therefore, aimed to investigate the expression of TGF-β1 in the context of H. pylori colonization in chronic gastritis, to examine the relationship between it and histopathologic findings and to compare it with virulence factors. PATIENTS AND METHODS Total RNA was extracted from gastric biopsies of 48 H. pylori-infected patients and 38 H. pylori-negative patients with gastritis. Mucosal TGF-β1 mRNA expression in H. pylori-infected and uninfected gastric biopsies was determined by real-time PCR. Presence of vacA, cagA, iceA, babA2 and oipA virulence factors was evaluated using PCR. RESULTS TGF-β1 mRNA expression was significantly increased in biopsies of H. pylori-infected patients compared to H. pylori-uninfected patients. There was association between virulence factors and TGF-β1 mRNA expression. TGF-β1 mRNA expression in mucosa was significantly higher in patients with vacA s1 and s1m1. CONCLUSIONS TGF-β1 may play an important role in the inflammatory response and promote the chronic and persistent inflammatory changes in the gastric. This may ultimately influence the outcome of H. pylori-associated diseases that arise within the context of gastritis and vacA may suffice to induce expression of TGF-β1 mRNA.
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Affiliation(s)
- Ghorbanali Rahimian
- Department of Internal Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | | | - Hedayatollah Shirzad
- Cellular and Molecular Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran.
| | | | - Afshin Taghikhani
- Department of Internal Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Loghman Salimzadeh
- Cellular and Molecular Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | | | | | - Nader Bagheri
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
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Feichtenbeiner A, Haas M, Büttner M, Grabenbauer GG, Fietkau R, Distel LV. Critical role of spatial interaction between CD8⁺ and Foxp3⁺ cells in human gastric cancer: the distance matters. Cancer Immunol Immunother 2014; 63:111-9. [PMID: 24170095 PMCID: PMC11029441 DOI: 10.1007/s00262-013-1491-x] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Accepted: 10/16/2013] [Indexed: 02/07/2023]
Abstract
PURPOSE In various cancer types, an abundance of FoxP3(+) regulatory T cells (Treg) has been associated with an unfavorable outcome. Yet, the role of Treg on cancer immunity has been shown to be complex. In single cell marker technique, other tumor-infiltrating lymphocytes (TILs) such as cytotoxic CD8(+) T cells (CTL) also influenced prognosis. This study for the first time investigates the concurrent spatial distribution pattern of CD8(+) and FoxP3(+) TILs and their prognostic impact in human gastric cancer. MATERIALS AND METHODS Tumor tissue microarrays of 50 patients with surgically treated adenocarcinoma of the cardia were studied. An immunohistochemical double staining of CD8(+) and FoxP3(+) TILs was performed. Cell counts and cell-to-cell distances in tumor epithelium and stroma were evaluated with image-processing software. Metastasis-free survival, no-evidence-of-disease survival, and overall survival were investigated (mean follow-up time 6.9 years). RESULTS High intraepithelial infiltration of CD8(+) and FoxP3(+) TIL was associated with the improved 10-year metastasis-free survival (83 vs. 54%, p = 0.04 and 85 vs. 59%, p = 0.09, respectively). Considering cell-to-cell distance and comparing patients with functional (30-110 μm) versus nonfunctional distances of CD8(+) and FoxP3(+) TILs, 10-year survival rates differed between 89 and 55% (p = 0.009), respectively. CONCLUSION Prognostic influence of tumor-infiltrating immune cells in gastric cancer critically depends on their cell-to-cell distance. FoxP3(+) TILs must be located within a distance between 30 and 110 μm of CD8(+) T cells to positively impact on prognosis.
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Affiliation(s)
- Anita Feichtenbeiner
- Department of Radiation Oncology of the University Hospitals, Friedrich-Alexander-University of Erlangen-Nürnberg, Universitätsstraße 27, 91054 Erlangen, Germany
| | - Matthias Haas
- Department of Radiology, Charité Universitätsmedizin, Berlin, Germany
| | - Maike Büttner
- Institute of Pathology of the University Hospitals, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Gerhard G. Grabenbauer
- Department of Radiation Oncology of the University Hospitals, Friedrich-Alexander-University of Erlangen-Nürnberg, Universitätsstraße 27, 91054 Erlangen, Germany
| | - Rainer Fietkau
- Department of Radiation Oncology of the University Hospitals, Friedrich-Alexander-University of Erlangen-Nürnberg, Universitätsstraße 27, 91054 Erlangen, Germany
| | - Luitpold V. Distel
- Department of Radiation Oncology of the University Hospitals, Friedrich-Alexander-University of Erlangen-Nürnberg, Universitätsstraße 27, 91054 Erlangen, Germany
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Won KY, Kim HS, Sung JY, Kim GY, Lee J, Park YK, Kim YW, Suh JH, Lim SJ. Tumoral FOXP3 has potential oncogenic function in conjunction with the p53 tumor suppressor protein and infiltrated Tregs in human breast carcinomas. Pathol Res Pract 2013; 209:767-73. [DOI: 10.1016/j.prp.2013.08.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Revised: 07/23/2013] [Accepted: 08/17/2013] [Indexed: 01/23/2023]
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Zhao J, Wang Z, Han J, Qiu X, Pan J, Chen J. Increased frequency of CD4+ CD25+ FOXP3+ cells correlates with the progression of 4-nitroquinoline1-oxide-induced rat tongue carcinogenesis. Clin Oral Investig 2013; 18:1725-30. [PMID: 24264641 PMCID: PMC4145201 DOI: 10.1007/s00784-013-1146-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2013] [Accepted: 11/13/2013] [Indexed: 12/15/2022]
Abstract
OBJECTIVES CD4+ CD25+ FoxP3+ T cells (Tregs) play an essential role in sustaining self-tolerance by negatively regulating immune responses. Increased frequencies of Tregs have been reported in a variety of human cancers. The aim of this study was to evaluate the prevalence of Tregs infiltration in the peripheral blood and regional lymph nodes during rat tongue carcinogenesis induced by 4-nitroquinoline-1-oxide (4NQO). MATERIALS AND METHODS Forty-eight Sprague-Dawley rats were divided into the control (n = 16) and experimental groups (n = 32) to which 4NQO in drinking water was administered. Flow cytometry was used to analyze the prevalence of Tregs in lymphocytes of peripheral blood and regional lymph nodes during 4NQO-induced rat tongue carcinogenesis. CD4+ CD25+ FoxP3+ cells were expressed as a percentage of the total CD4+ cells. RESULTS The frequency of Tregs in peripheral blood from squamous cell carcinoma rats was significantly higher than controls (3.82 ± 0.62 versus 1.40 ± 0.31 %, P < 0.001). The proportion of Tregs was sequentially increased from moderate dysplasia to severe dysplasia and SCC (1.94 ± 0.72, 2.29 ± 0.82, and 3.82 ± 0.62 %, respectively). The frequency of Tregs in regional lymph nodes from squamous cell carcinoma rats was also significantly higher than normal rat mucosa (14.67 ± 3.09 versus 5.53 ± 2.07 %, P < 0.001). The percentage of Tregs was gradually increased in moderate dysplasia, severe dysplasia, and SCC groups (8.93 ± 1.74, 10.15 ± 0.86, 14.67 ± 3.09 %, respectively) as compared to control group (5.53 ± 2.07 %). CONCLUSION AND CLINICAL RELEVANCE Tregs in peripheral blood and lymph nodes were associated with disease progression during 4NQO-induced rat tongue carcinogenesis. This study indicated that the upregulation of Tregs might play important role during oral mucosa malignant transformation.
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Affiliation(s)
- Jianjiang Zhao
- Department of Surgery, Guangdong Provincial Stomatological Hospital, Southern Medical University, Guangzhou, 510280, China,
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