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immunosuppressive microenvironment

Fangyuan Zhou, Bing Feng, Haijun Yu, Dangge Wang, Tingting Wang, Yuting Ma, Siling Wang, Yaping Li
Chemoimmunotherapy is reported to activate a robust T cell antitumor immune response by triggering immunogenic cell death (ICD), which has initiated a number of clinical trials. However, current chemoimmunotherapy is restricted to a small fraction of patients due to low drug delivery efficacy and immunosuppression within the tumor microenvironment. A tumor microenvironment-activatable prodrug vesicle for cancer chemoimmunotherapy using ICD is herein reported. The prodrug vesicles are engineered by integrating an oxaliplatin (OXA) prodrug and PEGylated photosensitizer (PS) into a single nanoplatform, which show tumor-specific accumulation, activation, and deep penetration in response to the tumoral acidic and enzymatic microenvironment...
February 14, 2019: Advanced Materials
R Domenis, A Cifù, M Fabris, F Curcio
No abstract text is available yet for this article.
July 2018: Journal of Biological Regulators and Homeostatic Agents
Neha M Sahasrabudhe, Joost C van der Horst, Vivian Spaans, Gemma Kenter, Cor de Kroon, Tjalling Bosse, Sandra J van Vliet, Ekaterina S Jordanova
Cervical cancer is the fourth most common cancer type in women worldwide and is characterized by a highly immune-suppressive microenvironment. Here, we describe aberrant glycosylation as a factor mediating this immunosuppressive microenvironment. Expression of a specific carbohydrate ligand for the immune-regulatory C-type lectin MGL was correlated to poor disease-specific survival and distant recurrences in squamous cell carcinoma (SCC) and adenosquamous carcinoma (ASC), the most common histological subtypes of cervical cancer...
2019: Frontiers in Oncology
Evangelos Terpos, Ioannis Ntanasis-Stathopoulos, Meletios A Dimopoulos
Bone disease is a cardinal complication of multiple myeloma that affects quality of life and survival. Osteocytes have emerged as key players in the development of myeloma-related bone disease. Along with other factors they participate in increased osteoclast activity, decreased osteoblast function and immunosuppressed marrow microenvironment that deregulate bone turnover and result in bone loss and skeletal-related events. Denosumab is a novel alternative to bisphosphonates against myeloma bone disease. Special considerations on this constantly evolving field are thoroughly discussed...
February 13, 2019: Blood
Miro K Viitala, Reetta Virtakoivu, Sina Tadayon, Jenna Rannikko, Sirpa Jalkanen, Maija Hollmén
PURPOSE: As foremost regulators of cancer-related inflammation and immunotherapeutic resistance, tumor-associated macrophages have garnered major interest as immunotherapeutic drug targets. However, depletory strategies have yielded little benefit in clinical studies to date. An alternative approach is to exploit macrophage plasticity and "reeducate" tumorigenic macrophages towards an immunostimulatory phenotype to activate the host's antitumor immunity. EXPERIMENTAL DESIGN: We investigated the role of macrophage scavenger receptor Clever-1 on tumor growth in multiple mouse cancer models with inflammatory and non-inflammatory characteristics by using conditional knockouts, bone marrow chimeras and cell depletion experiments...
February 12, 2019: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Sha Zhao, Shengxiang Ren, Tao Jiang, Bo Zhu, Xuefei Li, Chao Zhao, Yijun Jia, Jinpeng Shi, Limin Zhang, Xiaozhen Liu, Meng Qiao, Xiaoxia Chen, Chunxia Su, Hui Yu, Caicun Zhou, Jun Zhang, D Ross Camidge, Fred R Hirsch
Lack of response to treatment in most lung cancer patients suggests the value of broadening the benefit of anti-PD-1/PD-L1 monotherapy. Judicious dosing of anti-angiogenic agents such as apatinib (VEGFR2-TKI) can modulate the tumor immunosuppressive microenvironment, which contributes to resistance to anti-PD-1/PD-L1 treatment. We therefore hypothesized that inhibiting angiogenesis could enhance therapeutic efficacy of PD-1/PD-L1 blockade. Here, using a syngeneic lung cancer mouse model, we demonstrated that low-dose apatinib alleviated hypoxia, increased infiltration of CD8+ T cells, reduced recruitment of tumor-associated macrophages (TAMs) in tumor and decreased TGF-β amounts both in tumor and serum...
February 12, 2019: Cancer Immunology Research
Tina Gruosso, Mathieu Gigoux, Venkata Satya Kumar Manem, Nicholas Bertos, Dongmei Zuo, Irina Perlitch, Sadiq Mehdi Ismail Saleh, Hong Zhao, Margarita Souleimanova, Radia Marie Johnson, Anne Monette, Valentina Munoz Ramos, Michael Trevor Hallett, John Stagg, Réjean Lapointe, Atilla Omeroglu, Sarkis Meterissian, Laurence Buisseret, Gert Van den Eynden, Roberto Salgado, Marie-Christine Guiot, Benjamin Haibe-Kains, Morag Park
Understanding the tumor immune microenvironment (TIME) promises to be key for optimal cancer therapy, especially in triple-negative breast cancer (TNBC). Integrating spatial resolution of immune cells with laser capture microdissection gene expression profiles, we defined distinct TIME stratification in TNBC with implications for current therapies, including immune checkpoint blockade. TNBCs with an immunoreactive microenvironment exhibited tumoral infiltration of granzyme B+ CD8+ T cells, a type I interferon signature, elevated expression of multiple immune inhibitory molecules, including IDO, PD-L1, and good outcome...
February 12, 2019: Journal of Clinical Investigation
John D Martin, Giorgio Seano, Rakesh K Jain
Abnormal blood and lymphatic vessels create a hostile tumor microenvironment characterized by hypoxia, low pH, and elevated interstitial fluid pressure. These abnormalities fuel tumor progression, immunosuppression, and treatment resistance. In 2001, we proposed a novel hypothesis that the judicious use of antiangiogenesis agents-originally developed to starve tumors-could transiently normalize tumor vessels and improve the outcome of anticancer drugs administered during the window of normalization. In addition to providing preclinical and clinical evidence in support of this hypothesis, we also revealed the underlying molecular mechanisms...
February 10, 2019: Annual Review of Physiology
Junfei Zhao, Andrew X Chen, Robyn D Gartrell, Andrew M Silverman, Luis Aparicio, Tim Chu, Darius Bordbar, David Shan, Jorge Samanamud, Aayushi Mahajan, Ioan Filip, Rose Orenbuch, Morgan Goetz, Jonathan T Yamaguchi, Michael Cloney, Craig Horbinski, Rimas V Lukas, Jeffrey Raizer, Ali I Rae, Jinzhou Yuan, Peter Canoll, Jeffrey N Bruce, Yvonne M Saenger, Peter Sims, Fabio M Iwamoto, Adam M Sonabend, Raul Rabadan
Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders...
February 11, 2019: Nature Medicine
Shuo Huang, Zhongyu Wang, Jie Zhou, Jiani Huang, Li Zhou, Jing Luo, Yisong Y Wan, Haixia Long, Bo Zhu
Enhancer of Zeste homolog (EZH2) is a key epigenetic regulator of gene expression and is frequently overexpressed in various cancer types, suggesting a role in oncogenesis. The therapeutic potential of EZH2 inhibitors is currently being explored, but their effect on anti-tumor immunity is largely unknown. Here we report that suppressing EZH2 activity using EZH2 inhibitor GSK126 resulted in increased numbers of myeloid-derived suppressor cells (MDSC) and fewer CD4+ and IFN-γ+CD8+ T cells, which are involved in anti-tumor immunity...
February 8, 2019: Cancer Research
January Salas-Mckee, Weimin Kong, Whitney L Gladney, Julie K Jadlowsky, Gabriela Plesa, Megan M Davis, Joseph A Fraietta
The advent of engineered T cells as a form of immunotherapy marks the beginning of a new era in medicine, providing a transformative way to combat complex diseases such as cancer. Following FDA approval of CAR T cells directed against the CD19 protein for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma, CAR T cells are poised to enter mainstream oncology. Despite this success, a number of patients are unable to receive this therapy due to inadequate T cell numbers or rapid disease progression...
February 8, 2019: Human Vaccines & Immunotherapeutics
Jing Liu, Wenna Jiang, Kaili Zhao, Hongwei Wang, Tianxing Zhou, Weiwei Bai, Xiuchao Wang, Tiansuo Zhao, Chongbiao Huang, Song Gao, Tai Qin, Wenwen Yu, Bo Yang, Xin Li, Danqi Fu, Wei Tan, Shengyu Yang, He Ren, Jihui Hao
Pancreatic ductal adenocarcinoma (PDAC) is a highly immune-suppressive tumor with a low response rate to single checkpoint blockade therapy. ETS homologous factor (EHF) is a tumor suppressor in PDAC. Here, we report a novel function of EHF in pancreatic cancer immune microenvironment editing and efficacy prediction for anti-PD1 therapy. Our findings support that the deficiency of tumoral EHF induced the accumulation of regulatory T (T reg) cells and myeloid-derived suppressor cells (MDSCs) and a decrease in the number of tumor-infiltrating CD8+ T cells...
February 7, 2019: Journal of Experimental Medicine
Ioannis S Pateras, Tomer Cooks
Interactions between tumor cells and their microenvironment have been long established as a cardinal hallmark of tumorigenesis and metastasis. To that end, tumor-associated macrophages (TAMs) have been studied extensively and were found to be typically correlated with poor prognosis in various cancers. TAMs are key elements of cancer-associated inflammation promoting cancer progression by increasing angiogenesis, inducing immunosuppression of the tumor tissue, and remodeling the extracellular matrix favoring invasion and metastasis...
2019: Methods in Molecular Biology
Padma Kadiyala, Dan Li, Fernando M Nuñez, David Altshuler, Robert Doherty, Rui Kuai, Minzhi Yu, Neha Kamran, Marta Edwards, James J Moon, Pedro R Lowenstein, Maria G Castro, Anna Schwendeman
Glioblastoma multiforme (GBM) is an aggressive primary brain tumor, for which there is no cure. Treatment effectiveness for GBM has been limited due to tumor heterogeneity, an immunosuppressive tumor microenvironment (TME), and the presence of the blood-brain barrier, which hampers the transport of chemotherapeutic compounds to the central nervous system (CNS). High-density lipoprotein (HDL)-mimicking nanodiscs hold considerable promise to achieve delivery of bioactive compounds into tumors. Herein, we tested the ability of synthetic HDL nanodiscs to deliver chemotherapeutic agents to the GBM microenvironment and elicit tumor regression...
February 11, 2019: ACS Nano
Luis Rivera Sanchez, Lucia Borriello, David Entenberg, John S Condeelis, Maja H Oktay, George S Karagiannis
Macrophages represent a heterogeneous group of cells, capable of carrying out distinct functions in a variety of organs and tissues. Even within individual tissues, their functions can vary with location. Tumor-associated macrophages (TAMs) specialize into three major subtypes that carry out multiple tasks simultaneously. This is especially true in the context of metastasis, where TAMs establish most of the cellular and molecular prerequisites for successful cancer cell dissemination and seeding to the secondary site...
February 5, 2019: Journal of Leukocyte Biology
Pamela C Rosato, Sathi Wijeyesinghe, J Michael Stolley, Christine E Nelson, Rachel L Davis, Luke S Manlove, Christopher A Pennell, Bruce R Blazar, Clark C Chen, Melissa A Geller, Vaiva Vezys, David Masopust
The immunosuppressive tumor microenvironment limits the success of current immunotherapies. The host retains memory T cells specific for previous infections throughout the entire body that are capable of executing potent and immediate immunostimulatory functions. Here we show that virus-specific memory T cells extend their surveillance to mouse and human tumors. Reactivating these antiviral T cells can arrest growth of checkpoint blockade-resistant and poorly immunogenic tumors in mice after injecting adjuvant-free non-replicating viral peptides into tumors...
February 4, 2019: Nature Communications
Yahya Ashraf, Hanane Mansouri, Valérie Laurent-Matha, Lindsay B Alcaraz, Pascal Roger, Séverine Guiu, Danielle Derocq, Gautier Robin, Henri-Alexandre Michaud, Helène Delpech, Marta Jarlier, Martine Pugnière, Bruno Robert, Anthony Puel, Lucie Martin, Flavie Landomiel, Thomas Bourquard, Oussama Achour, Ingrid Fruitier-Arnaudin, Alexandre Pichard, Emmanuel Deshayes, Andrei Turtoi, Anne Poupon, Joëlle Simony-Lafontaine, Florence Boissière-Michot, Nelly Pirot, Florence Bernex, William Jacot, Stanislas du Manoir, Charles Theillet, Jean-Pierre Pouget, Isabelle Navarro-Teulon, Nathalie Bonnefoy, André Pèlegrin, Thierry Chardès, Pierre Martineau, Emmanuelle Liaudet-Coopman
BACKGROUND: Triple-negative breast cancer (TNBC) treatment is currently restricted to chemotherapy. Hence, tumor-specific molecular targets and/or alternative therapeutic strategies for TNBC are urgently needed. Immunotherapy is emerging as an exciting treatment option for TNBC patients. The aspartic protease cathepsin D (cath-D), a marker of poor prognosis in breast cancer (BC), is overproduced and hypersecreted by human BC cells. This study explores whether cath-D is a tumor cell-associated extracellular biomarker and a potent target for antibody-based therapy in TNBC...
February 4, 2019: Journal for Immunotherapy of Cancer
Takahiro Tsujikawa, Guillaume Thibault, Vahid Azimi, Sam Sivagnanam, Grace Banik, Casey Means, Rie Kawashima, Daniel R Clayburgh, Joe W Gray, Lisa M Coussens, Young Hwan Chang
Image cytometry enables quantitative cell characterization with preserved tissue architecture; thus, it has been highlighted in the advancement of multiplex immunohistochemistry (IHC) and digital image analysis in the context of immune-based biomarker monitoring associated with cancer immunotherapy. However, one of the challenges in the current image cytometry methodology is a technical limitation in the segmentation of nuclei and cellular components particularly in heterogeneously stained cancer tissue images...
February 4, 2019: Cytometry. Part A: the Journal of the International Society for Analytical Cytology
Yoko Tsukita, Tatsuma Okazaki, Satoru Ebihara, Riyo Komatsu, Mayumi Nihei, Makoto Kobayashi, Taizou Hirano, Hisatoshi Sugiura, Tsutomu Tamada, Nobuyuki Tanaka, Yasufumi Sato, Hideo Yagita, Masakazu Ichinose
Tumor-associated blood vessels and lymphatics are abnormal and dysfunctional. These are hallmarks of the tumor microenvironment, which has an immunosuppressive nature, such as through hypoxia. Treatment with anti-death receptor5 (DR5) monoclonal antibody MD5-1, which induces tumor cell death, is a potent anti-tumor immunotherapy. Generally, MD5-1 induces cell death mainly via antigen presenting cells (APCs) and generates tumor-specific effector T cells. To date, the effects of a simultaneous functional improvement of abnormal blood vessels and lymphatics on the immune microenvironment are largely unknown...
2019: Oncoimmunology
Asma A Elashi, Varun Sasidharan Nair, Rowaida Z Taha, Hibah Shaath, Eyad Elkord
Aberrant expression of immune checkpoints (ICs) in cancer creates an immunosuppressive microenvironment, which supports immune evasion of tumor cells. We have recently reported that epigenetic modifications are critical for ICs expression in the tumor microenvironment (TME) of primary breast cancer (PBC) and colorectal cancer (CRC). Herein, we investigated transcriptomic expression of ICs (PD-1, CTLA-4, LAG-3, TIM-3, TIGIT) and PD-L1 in peripheral blood of PBC and CRC patients, compared to healthy donors (HD)...
2019: Oncoimmunology
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