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immunosuppressive microenvironment

Ashraf Ishak Fawzy Tawadros, Mohamed Mohamed Mohamed Khalafalla
Background: Programmed death-ligand 1 (PD-L1) and hypoxia-inducible factor-1α (HIF-1α) proteins mediate major alterations of tumor microenvironment including generation of immunosuppressive microenvironment and tumor hypoxia, respectively. These alterations play a crucial role in carcinogenesis and tumor progression. Aims: The present study was designed to investigate the correlation between the expression of PD-L1 and HIF-1α proteins and the clinicopathologic variables in endometrial carcinoma...
December 2018: Journal of Cancer Research and Therapeutics
Nicholas J Protopsaltis, Wei Liang, Eric Nudleman, Napoleone Ferrara
TH 17 cells play important yet complex roles in cancer development and progression. We previously reported that TH 17 cells and IL-17 mediate resistance to anti-VEGF therapy by inducing recruitment of immunosuppressive and proangiogenic myeloid cells to the tumor microenvironment. Here, we demonstrate that IL-22, a key effector cytokine expressed by TH 17 cells, directly acts on endothelial cells to promote tumor angiogenesis. IL-22 induces endothelial cell proliferation, survival, and chemotaxis in vitro and neovascularization in an ex vivo mouse choroid explant model...
December 11, 2018: Angiogenesis
Alba Gonzalez-Junca, Kyla Driscoll, Ilenia Pellicciotta, Shisuo Du, Chen Hao Lo, Ritu Roy, Renate Parry, Iliana Tenvooren, Diana Marquez, Matthew H Spitzer, Mary Helen Barcellos-Hoff
Transforming growth factor β (TGFβ) is an effector of immune suppression and contributes to a permissive tumor microenvironment that compromises effective immunotherapy. We identified a correlation between TGFB1 and genes expressed by myeloid cells, but not granulocytes, in TCGA lung adenocarcinoma data, in which high TGFB1 expression was associated with poor survival. To determine whether TGFβ affected cell fate decisions and lineage commitment, we studied primary cultures of CD14+ monocytes isolated from peripheral blood of healthy donors...
December 11, 2018: Cancer Immunology Research
Xiaofan Guo, Wei Qiu, Jian Wang, Qinglin Liu, Mingyu Qian, Shaobo Wang, Zongpu Zhang, Xiao Gao, Zihang Chen, Qindong Guo, Jianye Xu, Hao Xue, Gang Li
Myeloid-derived suppressor cells (MDSCs) play a pivotal role in mediating the formation of an immunosuppressive environment and assisting tumors in evading the host immune response. However, the mechanism through which tumors manipulate the differentiation and function of MDSCs remains unclear. Here, we report that hypoxia-induced glioma cells can stimulate the differentiation of functional MDSCs by transferring exosomal miR-29a and miR-92a to MDSCs. Our results showed that glioma-derived exosomes (GEXs) can enhance the differentiation of functional MDSCs both in vitro and in vivo, and hypoxia-induced GEXs (H-GEXs) demonstrated a stronger MDSCs induction ability than did normoxia-induced GEXs (N-GEXs)...
December 11, 2018: International Journal of Cancer. Journal International du Cancer
Malak Abedalthagafi, Duna Barakeh, Kara M Foshay
The prognosis of glioblastoma has changed little over the past two decades, with only minor improvements in length of overall survival through the addition of temozolomide (temodal) to standard of care and the recommended use of alternating electric field therapy (optune) to newly diagnosed patients. In an effort to define novel therapeutic targets across molecularly heterogeneous disease subgroups, researchers have begun to uncover the complex interplay between epigenetics, cell signaling, metabolism, and the immunosuppressive tumor microenvironment...
2018: NPJ Precision Oncology
Gi-Ho Sung, Hyun Chang, Ji-Yong Lee, Si Young Song, Han-Soo Kim
Pancreatic cancer is a challenging disease with a high mortality rate. While the importance of crosstalk between cancer and immune cells has been well documented, the understanding of this complex molecular network is incomplete. Thus, identification of the secreted proteins contributing to the immunosuppressive microenvironment in pancreatic cancer is crucial for effective diagnosis and/or therapy. We utilized a public microarray dataset (GSE16515) from the Gene Expression Omnibus database to identify genes for secreted proteins in pancreatic cancer...
2018: Animal Cells and Systems
Yingna Chen, Lei Bi, Huijuan Luo, Yucui Jiang, Feiyan Chen, Yunshan Wang, Guangwei Wei, Weiping Chen
ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine, supplementing Qi and strengthening body resistance are an important principle of anticancer treatment. Panax ginseng C.A.Mey. (ginseng) and Astragalus membranaceus Bunge (astragalus) are the representative herbs for this therapeutic principle. AIM OF THE STUDY: This study aims to explore the effect of the water extract of ginseng and astragalus (WEGA) on regulating macrophage polarization and mediating anticancer in the tumor microenvironment...
December 5, 2018: Journal of Ethnopharmacology
Yichen Chen, Xi Wang, Juan Fang, Jingjing Song, Da Ma, Liqun Luo, Bailin He, Juan Xia, Vivian Wai Yan Lui, Bin Cheng, Zhi Wang
Recent evidences suggested that Mesenchymal stem cells (MSCs) may be involved in tumor formation by modulating of the tumor microenvironment, but it is still unclear the potential of MSCs in the malignant transformation of oral mucosa. Using a chemically-induced oral carcinogenesis model by 4-nitroquinoline-1-oxide (4NQO), we generated precancerous lesions and cancerous lesions in the oral cavity of rats. Flow cytometric analysis on lesions derived single cell suspension revealed an increase in the proportion of MSCs and a decreased proportion of T cell during oral mucosa malignancy...
December 4, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Gang Shi, Qianmei Yang, Yujing Zhang, Qingyuan Jiang, Yi Lin, Shenshen Yang, Huiling Wang, Lin Cheng, Xin Zhang, Yimin Li, Qingnan Wang, Yi Liu, Qin Wang, Hantao Zhang, Xiaolan Su, Lei Dai, Lei Liu, Shuang Zhang, Jia Li, Zhi Li, Yang Yang, Dechao Yu, Yuquan Wei, Hongxin Deng
Immunotherapy based on the immune checkpoint blockade has emerged as the most promising approach for cancer therapy. However, the proportion of colorectal cancer patients who benefit from immunotherapy is small due to the immunosuppressive tumor microenvironment. Hence, combination immunotherapy is an ideal strategy to overcome this limitation. In this study, we developed a novel combination of CSF-1R (colony-stimulating factor 1 receptor) inhibitor (PLX3397), oncolytic viruses, and anti-PD-1 antibody. Our results demonstrated that the triple treatment synergistically conferred significant tumor control and prolonged the survival of mouse models of colon cancer...
November 17, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Takashi Sakai, Keiju Aokage, Shinya Neri, Hiroshi Nakamura, Shogo Nomura, Kenta Tane, Tomohiro Miyoshi, Masato Sugano, Motohiro Kojima, Satoshi Fujii, Takeshi Kuwata, Atsushi Ochiai, Akira Iyoda, Masahiro Tsuboi, Genichiro Ishii
OBJECTIVES: Podoplanin-positive cancer-associated fibroblasts [PDPN (+) CAFs] play an important role in cancer progression in non-small-cell lung cancer. The aim of this study was to clarify the correlation between a fibrous microenvironment containing PDPN (+) CAFs and an immune microenvironment. MATERIALS AND METHODS: A total of 174 patients with pathological stage I lung adenocarcinoma were analyzed. We evaluated PDPN (+) CAFs and immune-related cells, CD 204-positive tumor-associated macrophages [CD204 (+) TAMs], CD8-positive T cells, and FOXP3-positive T cells, in cancer stroma by using immunohistochemical staining...
December 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Takuya Ueda, Keiju Aokage, Sachiyo Mimaki, Kenta Tane, Tomohiro Miyoshi, Masato Sugano, Motohiro Kojima, Satoshi Fujii, Takeshi Kuwata, Atsushi Ochiai, Masahiko Kusumoto, Kenji Suzuki, Katsuya Tsuchihara, Hiroyoshi Nishikawa, Koichi Goto, Masahiro Tsuboi, Genichiro Ishii
BACKGROUND: Lung cancer with usual interstitial pneumonia (UIP) pattern is a disease with poor prognosis. This study aimed to characterize the tumor microenvironment of lung adenocarcinoma associated with UIP (UIP-ADC). METHODS: A total of 1341 consecutive patients with ADC who had undergone complete surgical resection were enrolled in this study, and the clinicopathological features of UIP-ADC were examined. Further, we selected 17 cases of UIP-ADC and non-UIP ADC each (adjusted for age, smoking status, pathological stage, and invasive size of lesion) for immunohistochemical analysis, and the biological differences between UIP-ADC and non-UIP ADC groups were analyzed...
December 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Linsen Ye, Qi Zhang, Yusheng Cheng, Xiaolong Chen, Guoying Wang, Mengchen Shi, Tong Zhang, Yingjiao Cao, Hang Pan, Liting Zhang, Genshu Wang, Yinan Deng, Yang Yang, Guihua Chen
BACKGROUND: Regulatory B (Breg) cells represent one of the B cell subsets that infiltrate solid tumors and exhibit distinct phenotypes in different tumor microenvironments. However, the phenotype, function and clinical relevance of Breg cells in human hepatocellular carcinoma (HCC) are presently unknown. METHODS: Flow cytometry analyses were performed to determine the levels, phenotypes and functions of TIM-1+ Breg cells in samples from 51 patients with HCC. Kaplan-Meier plots for overall survival and disease-free survival were generated using the log-rank test...
December 10, 2018: Journal for Immunotherapy of Cancer
Lucillia Bezu, Oliver Kepp, Giulia Cerrato, Jonathan Pol, Jitka Fucikova, Radek Spisek, Laurence Zitvogel, Guido Kroemer, Lorenzo Galluzzi
Peptide-based anticancer vaccination aims at stimulating an immune response against one or multiple tumor-associated antigens (TAAs) following immunization with purified, recombinant or synthetically engineered epitopes. Despite high expectations, the peptide-based vaccines that have been explored in the clinic so far had limited therapeutic activity, largely due to cancer cell-intrinsic alterations that minimize antigenicity and/or changes in the tumor microenvironment that foster immunosuppression. Several strategies have been developed to overcome such limitations, including the use of immunostimulatory adjuvants, the co-treatment with cytotoxic anticancer therapies that enable the coordinated release of damage-associated molecular patterns, and the concomitant blockade of immune checkpoints...
2018: Oncoimmunology
Hanyong Sun, Weiqin Yang, Yuan Tian, Xuezhen Zeng, Jingying Zhou, Myth T S Mok, Wenshu Tang, Yu Feng, Liangliang Xu, Anthony W H Chan, Joanna H Tong, Yue-Sun Cheung, Paul B S Lai, Hector K S Wang, Shun-Wa Tsang, King-Lau Chow, Mengying Hu, Rihe Liu, Leaf Huang, Bing Yang, Pengyuan Yang, Ka-Fai To, Joseph J Y Sung, Grace L H Wong, Vincent W S Wong, Alfred S L Cheng
Obesity increases the risk of hepatocellular carcinoma (HCC) especially in men, but the molecular mechanism remains obscure. Here, we show that an androgen receptor (AR)-driven oncogene, cell cycle-related kinase (CCRK), collaborates with obesity-induced pro-inflammatory signaling to promote non-alcoholic steatohepatitis (NASH)-related hepatocarcinogenesis. Lentivirus-mediated Ccrk ablation in liver of male mice fed with high-fat high-carbohydrate diet abrogates not only obesity-associated lipid accumulation, glucose intolerance and insulin resistance, but also HCC development...
December 6, 2018: Nature Communications
Biagio Ricciuti, Giulia Costanza Leonardi, Paolo Puccetti, Francesca Fallarino, Vanessa Bianconi, Amirhossein Sahebkar, Sara Baglivo, Rita Chiari, Matteo Pirro
Immunotherapy through immune checkpoint blockers (ICBs) is quickly transforming cancer treatment by improving patients' outcomes. However, innate and acquired resistance to ICBs remain a major challenge in clinical settings. Indoleamine 2,3-dioxygenases (IDOs) are enzymes involved in tryptophan catabolism with a central immunosuppressive function within the tumor microenvironment. IDOs are over-expressed in cancer patients and have increasingly been associated with worse outcomes and a poor prognosis. Preclinical data have shown that combining IDO and checkpoint inhibition might be a valuable strategy to improve the efficacy of immunotherapy...
December 3, 2018: Pharmacology & Therapeutics
Haoran Zha, Xinxin Wang, Ying Zhu, Dian-Gang Chen, Xiao Han, Fei Yang, Jianbao Gao, Chunyan Hu, Chi Shu, Yi Feng, Yulong Tan, Jinyu Zhang, Yongsheng Li, Yisong Y Wan, Bo Guo, Bo Zhu
Complement aids in the construction of an immunosuppressive tumor microenvironment (TME). Tumor cell-derived C3 has been previously reported, but whether and how it acts on antitumor immunity remains to be elucidated. Here, we describe a mechanism for tumor cell-derived C3 in suppressing antitumor immunity. Tumor cell-derived C3 was activated intracellularly, which results in generation of C3a. C3a modulated tumor-associated macrophages (TAMs) via C3a-C3aR-PI3Kγ signaling, thereby repressing antitumor immunity...
December 4, 2018: Cancer Immunology Research
Paul E Clavijo, Jay Friedman, Yvette Robbins, Ellen C Moore, Ernest S Smith, Maurice Zauderer, Elizabeth E Evans, Clint T Allen
Tumor infiltration by immunosuppressive myeloid cells, such as myeloid-derived suppressor cells (MDSCs), causes resistance to immunotherapy. Semaphorin4D, originally characterized for its axonal guidance properties, also contributes to endothelial cell migration and survival and modulates global immune cytokine profiles and myeloid cell polarization within the tumor microenvironment. Here, we show how a therapeutic murine Sema4D mAb improves responses to immune checkpoint blockade in two murine carcinoma models...
December 4, 2018: Cancer Immunology Research
Jiao Wang, Kyle B Lupo, Andrea M Chambers, Sandro Matosevic
BACKGROUND: The anti-tumor immunity of natural killer (NK) cells can be paralyzed by the CD73-induced generation of immunosuppressive adenosine from precursor ATP within the hypoxic microenvironment of solid tumors. In an effort to redirect purinergic immunosuppression of NK cell anti-tumor function, we showed, for the first time, that immunometabolic combination treatment with NKG2D-engineered CAR-NK cells alongside blockade of CD73 ectonucleotidase activity can result in significant anti-tumor responses in vivo...
December 4, 2018: Journal for Immunotherapy of Cancer
Kevin Sek, Christina Mølck, Gregory D Stewart, Lev Kats, Phillip K Darcy, Paul A Beavis
The immune system plays a major role in the surveillance and control of malignant cells, with the presence of tumor infiltrating lymphocytes (TILs) correlating with better patient prognosis in multiple tumor types. The development of 'checkpoint blockade' and adoptive cellular therapy has revolutionized the landscape of cancer treatment and highlights the potential of utilizing the patient's own immune system to eradicate cancer. One mechanism of tumor-mediated immunosuppression that has gained attention as a potential therapeutic target is the purinergic signaling axis, whereby the production of the purine nucleoside adenosine in the tumor microenvironment can potently suppress T and NK cell function...
December 2, 2018: International Journal of Molecular Sciences
Pia S Zeiner, Corinna Preusse, Anna Golebiewska, Jenny Zinke, Ane Iriondo, Arnaud Muller, Tony Kaoma, Katharina Filipski, Monika Müller-Eschner, Simon Bernatz, Anna-Eva Blank, Peter Baumgarten, Elena Ilina, Anne Grote, Martin L Hansmann, Marcel A Verhoff, Kea Franz, Friedrich Feuerhake, Joachim P Steinbach, Jörg Wischhusen, Werner Stenzel, Simone P Niclou, Patrick N Harter, Michel Mittelbronn
While the central nervous system is considered an immunoprivileged site and brain tumors display immunosuppressive features, both innate and adaptive immune responses affect glioblastoma (GBM) growth and treatment resistance. However, the impact of the major immune cell population in gliomas, represented by glioma-associated microglia/macrophages (GAMs), on patients' clinical course is still unclear. Thus, we aimed at assessing the immunohistochemical expression of selected microglia and macrophage markers in 344 gliomas (including gliomas from WHO grade I-IV)...
December 3, 2018: Brain Pathology
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