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immunosuppressive microenvironment

Masoud Najafi, Bagher Farhood, Keywan Mortezaee
Regulatory T cells (Tregs) represent a low number of T-cell population under normal conditions, and they play key roles for maintaining immune system in homeostasis. The number of these cells is extensively increased in nearly all cancers, which is for dampening responses from immune system against cancer cells, metastasis, tumor recurrence, and treatment resistance. The interesting point is that apoptotic Tregs are stronger than their live counterparts for suppressing responses from immune system. Tregs within the tumor microenvironment have extensive positive cross-talks with other immunosuppressive cells including cancer-associated fibroblasts, cancer cells, macrophage type 2 cells, and myeloid-derived suppressor cells, and they have negative interactions with immunostimulatory cells including cytotoxic T lymphocytes (CTL) and natural killer cells...
October 14, 2018: Journal of Cellular Physiology
Nazli Jafarzadeh, Zohreh Safari, Majid Pornour, Naser Amirizadeh, Mehdi Forouzandeh Moghadam, Majid Sadeghizadeh
Leukemic cells can impact the bone marrow niche to create a tumor-favorable microenvironment using their secreted factors. Little knowledge is available about immunosuppressive and tumor-promoting properties of chronic myeloid leukemia derived exosomes in bone marrow stromal components. We report here that K562-derived exosomes can affect the gene expression, cytokine secretion, nitric oxide (NO) production, and redox potential of bone marrow mesenchymal stem cells (BM-MSCs) and macrophages. Human BM-MSCs and mouse macrophages were treated with K562-derived exosomes...
October 14, 2018: Journal of Cellular Physiology
Shuai Zhen, Jiaojiao Lu, Ling Hua, Yun-Hui Liu, Wei Chen, Xu Li
Targeted therapy results in objective responses in cervical cancer. However, the responses are short. In contrast, treatment with immune checkpoint inhibitors results in a lower responses rate, but the responses tend to be more durable. Based on these findings, we hypothesized that HPV16 E6/E7-targeted therapy may synergize with the PD-1 pathway blockade to enhance antitumor activity. To test the hypothesis, we described the effects of CRISPR/Cas9 which targeted to the HPV and PD1 in vitro and in vivo. Our data showed that gRNA/cas9 targeted HPV16 E6/E7 induced cervical cancer cell SiHa apoptosis, and suggested that overexpression of PD-L1, induced by HPV16 E6/E7, may be responsible for lymphocyte dysfunction...
October 10, 2018: Archives of Biochemistry and Biophysics
Yasuko Tada, Yosuke Togashi, Daisuke Kotani, Takeshi Kuwata, Eichi Sato, Akihito Kawazoe, Toshihiko Doi, Hisashi Wada, Hiroyoshi Nishikawa, Kohei Shitara
BACKGROUND: Several studies have established a correlation between the VEGF-VEGFR2 axis and an immunosuppressive microenvironment; this immunosuppression can be overcome by anti-angiogenic reagents, such as ramucirumab (RAM). However, little is known about the immunological impact of anti-angiogenic reagents within the tumor microenvironment in human clinical samples. This study aimed at investigating the effects of RAM on the tumor microenvironmental immune status in human cancers. METHODS: We prospectively enrolled 20 patients with advanced gastric cancer (GC) who received RAM-containing chemotherapy...
October 11, 2018: Journal for Immunotherapy of Cancer
Tsuyoshi Hamada, Jonathan A Nowak, Yohei Masugi, David A Drew, Mingyang Song, Yin Cao, Keisuke Kosumi, Kosuke Mima, Tyler S Twombly, Li Liu, Yan Shi, Annacarolina da Silva, Mancang Gu, Wanwan Li, Katsuhiko Nosho, NaNa Keum, Marios Giannakis, Jeffrey A Meyerhardt, Kana Wu, Molin Wang, Andrew T Chan, Edward L Giovannucci, Charles S Fuchs, Reiko Nishihara, Xuehong Zhang, Shuji Ogino
Background: Evidence indicates not only carcinogenic effect of cigarette smoking but also its immunosuppressive effect. We hypothesized that the association of smoking with colorectal cancer risk might be stronger for tumors with lower anti-tumor adaptive immune response. Methods: During follow-up of 134 981 participants (3 490 851 person-years) in the Nurses' Health Study and Health Professionals Follow-up Study, we documented 729 rectal and colon cancer cases with available data on T-cell densities in tumor microenvironment...
October 11, 2018: Journal of the National Cancer Institute
Yaping Wang, Xiaoyun Yang, Xiaoyan Sun, Liucheng Rong, Meiyun Kang, Peng Wu, Xiaohui Ji, Rufeng Lin, Jie Huang, Yao Xue, Yongjun Fang
Immune escape due to immunosuppressive microenvironments, such as those associated with regulatory T (Treg) cells is highly associated with initial occurrence and development of solid tumors or hematologic malignancies. Here, we employed high-throughput transcriptome screening to demonstrate immunosuppression-associated increases in the long noncoding (lnc) RNA lnc-insulin receptor precursor (INSR), which was corrected with INSR expression in CD4+ T cells extracted from the bone marrow of patients with childhood acute T lymphoblastic leukemia...
October 11, 2018: Cell Death & Disease
Naike Casagrande, Cinzia Borghese, Lydia Visser, Maurizio Mongiat, Alfonso Colombatti, Donatella Aldinucci
Classic Hodgkin lymphoma tumor cells express a functional CCR5 receptor, and tumor tissues express high CCL5 levels, suggesting that CCL5-CCR5 signaling is involved in tumor-microenvironment formation and tumor growth. Using the CCR5 antagonist maraviroc and a neutralizing anti-CCL5 antibody, we found that CCL5 secreted by Classic Hodgkin lymphoma cells recruited Mesenchymal-stromal cells and monocytes. Education of Mesenchymal-stromal cells by tumor cell conditioned medium enhanced Mesenchymal-stromal cells proliferation and CCL5 secretion...
October 11, 2018: Haematologica
Sergey N Zolov, Skyler P Rietberg, Challice L Bonifant
Targeted adoptive immunotherapy with engineered T cells is a promising treatment for refractory hematologic malignancies. However, many patients achieving early complete remissions ultimately relapse. Immunosuppressive ligands are expressed on tumor and supportive cells in the tumor microenvironment (TME). When activated, T cells express associated "checkpoint" receptors. Binding of co-inhibitory ligands and receptors may directly contribute to T-cell functional exhaustion. It is not known whether all T cells engineered to express chimeric antigen receptors (CARs) are subject to checkpoint-mediated regulation...
October 8, 2018: Cytotherapy
Ramin Lotfi, Lena Steppe, Regina Hang, Markus Rojewski, Marina Massold, Bernd Jahrsdörfer, Hubert Schrezenmeier
INTRODUCTION: MSCs are often found within tumors, promote cancer progression and enhance metastasis. MSCs can act as immuosuppressive cells, partially due to the expression of the enzyme indoleamine dioxygenase (IDO) which converts tryptophan to kynurenine. Decreased concentration of tryptophan and increased kynurenine, both interfere with effective immune response. Damage associated molecular patterns (DAMPs) including ATP are found within the tumor microenvironment, attract MSCs, and influence their biology...
October 10, 2018: Immunity, Inflammation and Disease
Sandro Matosevic
Natural killer (NK) cells are powerful immune effectors whose antitumor activity is regulated through a sophisticated network of activating and inhibitory receptors. As effectors of cancer immunotherapy, NK cells are attractive as they do not attack healthy self-tissues nor do they induce T cell-driven inflammatory cytokine storm, enabling their use as allogeneic adoptive cellular therapies. Clinical responses to adoptive NK-based immunotherapy have been thwarted, however, by the profound immunosuppression induced by the tumor microenvironment, particularly severe in the context of solid tumors...
2018: Journal of Immunology Research
Hiroshi Fujiwara
In cancer immunotherapy, the importance of tumor microenvironment (TME) has recently been highlighted. TME, where trafficked T lymphocytes with tumoricidal activity, particularly endowed by dendritic cells in the sentinel lymph nodes, suppress cancer cells, consists of multiple cellular components, such as fibroblasts, macrophages, myeloid-derived suppressor cells, monocytes, neutrophils, regulatory T cells, and NK cells, and non-cellular components, such as extracellular matrix and blood and lymphatic vessels...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Rosario García-Rocha, Alberto Monroy-García, Jorge Hernández-Montes, Benny Weiss-Steider, Vianey Gutiérrez-Serrano, María Del Carmen Fuentes-Castañeda, Luis Roberto Ávila-Ibarra, Christian Azucena Don-López, Daniela Berenice Torres-Pineda, María de Lourdes Mora-García
In cancer, the adenosinergic pathway participates in the generation of an immunosuppressive microenvironment and in the promotion of tumor growth through the generation of adenosine (Ado). The present study analyzed the participation of Ado, generated through the functional activity of the cervical cancer (CeCa) pathway in CeCa cells, to induce the expression and secretion of TGF-β1, as well as the participation of this factor to maintain CD73 expression. Ado concentrations greater than 10 μM were necessary to induce an increase of over 50% in the production and expression of TGF-β1 in CeCa tumor cells...
October 6, 2018: Cytokine
Jinyu Zhang, Haochen Jiang, Haiyun Zhang
BACKGROUND: Recent advances in cancer immunotherapy suggest a possibility of harnessing the immune system to defeat malignant tumors, but the complex immunosuppressive microenvironment confines the therapeutic benefits to a minority of patients with solid tumors. METHODS: A lentivector-based inducible system was established to evaluate the therapeutic effect of cytokines in established tumors. Intratumoral injection of certain cytokine combination in syngeneic tumor models was conducted to assess the therapeutic potentials...
October 5, 2018: EBioMedicine
Ryuma Tokunaga, Shu Cao, Madiha Naseem, Jae Ho Lo, Francesca Battaglin, Alberto Puccini, Martin D Berger, Shivani Soni, Joshua Millstein, Wu Zhang, Sebastian Stintzing, Fotios Loupakis, Chiara Cremolini, Volker Heinemann, Alfredo Falcone, Heinz-Josef Lenz
BACKGROUND: Adenosine has an immunosuppressive and angiogenic modulation of the tumor microenvironment. The present study explored the efficacy of single nucleotide polymorphisms (SNPs) in adenosine-related molecules for patients with metastatic colorectal cancer treated with bevacizumab-based chemotherapy. PATIENTS AND METHODS: We analyzed genomic DNA extracted from 451 samples from 3 independent cohorts: a discovery cohort of 107 patients treated with FOLFIRI (5-fluorouracil, leucovorin, oxaliplatin, irinotecan) plus bevacizumab in FIRE-3 (ClinicalTrials...
September 13, 2018: Clinical Colorectal Cancer
Bianca Simon, Ugur Uslu
Chimeric antigen receptor (CAR)-T cells are one of the impressive recent success stories of anti-cancer immunotherapy. Especially in hematological malignancies this treatment strategy has shown promising results leading to the recent approval of two CAR-T cell constructs targeting CD19 in the United States and the European Union. After the huge success in hematological cancers, the next step will be the evaluation of its efficacy in different solid tumors, which is currently investigated in preclinical as well as clinical settings...
October 4, 2018: Experimental Dermatology
Sahil Gupta, Arpit Jain, Shahzad Nawaz Syed, Ryan G Snodgrass, Beatrice Pflüger-Müller, Matthias S Leisegang, Andreas Weigert, Ralf P Brandes, Ingo Ebersberger, Bernhard Brüne, Dmitry Namgaladze
Macrophages in the tumor microenvironment respond to complex cytokine signals. How these responses shape the phenotype of tumor-associated macrophages (TAMs) is incompletely understood. Here we explored how cytokines of the tumor milieu, interleukin (IL)-6 and IL-4, interact to influence target gene expression in primary human monocyte-derived macrophages (hMDMs). We show that dual stimulation with IL-4 and IL-6 synergistically modified gene expression. Among the synergistically induced genes are several targets with known pro-tumorigenic properties, such as CC-chemokine ligand 18 (CCL18), transforming growth factor alpha (TGFA) or CD274 (programmed cell death 1 ligand 1 (PD-L1))...
2018: Oncoimmunology
Isabella Reccia, Jayant Kumar, Nagy Habib, Mikael Sodergren
Despite significant improvement in treatment, the prognosis of pancreatic ductal adenocarcinoma remains poor as the biology of the tumour affects survival even when a radical resection has been performed. Pancreatic cancer remains resistant to currently available chemotherapeutic options. Recently, immunotherapy has achieved significant results in certain types of cancer. However, for pancreatic cancer, results were not initially encouraging as pancreatic cancer microenvironment is highly immunosuppressive...
October 4, 2018: Medical Oncology
Paola Kučan Brlić, Tihana Lenac Roviš, Guy Cinamon, Pini Tsukerman, Ofer Mandelboim, Stipan Jonjić
Poliovirus receptor (PVR, CD155) has recently been gaining scientific interest as a therapeutic target in the field of tumor immunology due to its prominent endogenous and immune functions. In contrast to healthy tissues, PVR is expressed at high levels in several human malignancies and seems to have protumorigenic and therapeutically attractive properties that are currently being investigated in the field of recombinant oncolytic virotherapy. More intriguingly, PVR participates in a considerable number of immunoregulatory functions through its interactions with activating and inhibitory immune cell receptors...
October 1, 2018: Cellular & Molecular Immunology
Masoud Najafi, Nasser Hashemi Goradel, Bagher Farhood, Eniseh Salehi, Maryam Shabani Nashtaei, Neda Khanlarkhani, Zahra Khezri, Jamal Majidpoor, Morteza Abouzaripour, Mohsen Habibi, Iraj Ragerdi Kashani, Keywan Mortezaee
Macrophages are the most abundant cells within the tumor stroma displaying noticeable plasticity, which allows them to perform several functions within the tumor microenvironment. Tumor-associated macrophages commonly refer to an alternative M2 phenotype, exhibiting anti-inflammatory and pro-tumoral effects. M2 cells are highly versatile and multi-tasking cells that directly influence multiple steps in tumor development, including cancer cell survival, proliferation, stemness, and invasiveness along with angiogenesis and immunosuppression...
September 30, 2018: Journal of Cellular Biochemistry
Viviana Cremasco, Jillian L Astarita, Angelo L Grauel, Shilpa Keerthivasan, Kenzie D MacIsaac, Matthew C Woodruff, Michael Wu, Lotte Spel, Stephen Santoro, Zohreh Amoozgar, Tyler Laszewski, Sara Cruz-Migoni, Konstantin Knoblich, Anne L Fletcher, Martin LaFleur, Kai W Wucherpfennig, Ellen Pure, Glenn Dranoff, Michael Carroll, Shannon J Turley
Cancer-associated fibroblasts (CAFs) are generally associated with poor clinical outcome. CAFs support tumor growth in a variety of ways and can suppress antitumor immunity and response to immunotherapy. However, a precise understanding of CAF contributions to tumor growth and therapeutic response is lacking. Discrepancies in this field of study may stem from heterogeneity in composition and function of fibroblasts in the tumor microenvironment. Furthermore, it remains unclear whether CAFs directly interact with and suppress T cells...
September 28, 2018: Cancer Immunology Research
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