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immunosuppressive microenvironment

Michael C Comiskey, Matthew C Dallos, Charles G Drake
Immunotherapy is rapidly transforming cancer care across a range of tumor types. Although Sipuleucel-T represented the first successful vaccine for the treatment of established cancer, other immunotherapeutic approaches for prostate cancer such as checkpoint inhibitors have been relatively disappointing to date. However, significant promise is on the horizon as there is a wide array trials evaluating immunotherapy in prostate cancer patients. These include both immune checkpoint inhibitors and antigen-specific approaches including vaccines, antibody-drug conjugates, and antitumor antibodies...
August 18, 2018: Current Oncology Reports
Daniel S Chen, Herbert Hurwitz
Cancer immunotherapy (CIT) has transformed cancer treatment. In particular, immunotherapies targeting the programmed death ligand 1 (PD-L1)/programmed death 1 pathway have demonstrated durable clinical benefit in some patients. However, CIT combinations may create a more favorable environment in which to maximize the potential of the immune system to eliminate cancer. Here we describe 3 key mechanisms related to vascular endothelial growth factor (VEGF)-mediated immunosuppression: inhibition of dendritic cell maturation, reduction of T-cell tumor infiltration, and promotion of inhibitory cells in the tumor microenvironment; supporting data are also described...
July 2018: Cancer Journal
Kaustubh Datta, Sohini Roy, Arup K Bag, Samikshan Dutta, Navatha Shree Polavaram, Ridwan Islam, Samuel Schellenburg, Jasjit K Banwait, Chittibabu Guda, Sophia Ran, Michael A Hollingsworth, Rakesh K Singh, James E Talmadge, Michael H Muders, Surinder K Batra
Tumor-associated macrophages (TAM) are causally associated with tumorigenesis as well as regulation of anti-tumor immune responses and have emerged as potential immunotherapeutic targets. Recent evidence suggests TAM phagocytose apoptotic tumor cells within the tumor microenvironment (TME) through efferocytosis in an immunologically silent manner, thus maintaining an immunosuppressed microenvironment. The signal transduction pathways coupling efferocytosis and immunosuppression are not well known. Neuropilin-2 (NRP2) is member of the membrane-associated neuropilin family and has been reported in different immune cells but is poorly characterized...
August 15, 2018: Cancer Research
E Jane Homan, Robert D Bremel
Helminth infections, by nematodes, trematodes, or cestodes, can lead to the modulation of host immune responses. This allows long-duration parasite infections and also impacts responses to co-infections. Surface, secreted, excreted, and shed proteins are thought to play a major role in modulation. A commonly reported feature of such immune modulation is the role of T regulatory (Treg) cells and IL-10. Efforts to identify helminth proteins, which cause immunomodulation, have identified candidates but not provided clarity as to a uniform mechanism driving modulation...
2018: Frontiers in Immunology
Chun-Yu Chen, Brian Hutzen, Mary F Wedekind, Timothy P Cripe
Oncolytic viruses are lytic for many types of cancers but are attenuated or replication-defective in normal tissues. Aside from tumor lysis, oncolytic viruses can induce host immune responses against cancer cells and may thus be viewed as a form of immunotherapy. Although recent successes with checkpoint inhibitors have shown that enhancing antitumor immunity can be effective, the dynamic nature of the immunosuppressive tumor microenvironment presents significant hurdles to the broader application of these therapies...
2018: Oncolytic Virotherapy
Inigo Martinez-Zubiaurre, Anthony J Chalmers, Turid Hellevik
The implementation of novel cancer immunotherapies in the form of immune checkpoint blockers represents a major advancement in the treatment of cancer, and has renewed enthusiasm for identifying new ways to induce antitumor immune responses in patients. Despite the proven efficacy of neutralizing antibodies that target immune checkpoints in some refractory cancers, many patients do not experience therapeutic benefit, possibly owing to a lack of antitumor immune recognition, or to the presence of dominant immunosuppressive mechanisms in the tumor microenvironment (TME)...
2018: Frontiers in Immunology
Nkechiyere G Nwani, Livia E Sima, Wilberto Nieves-Neira, Daniela Matei
Cancer⁻stroma interactions play a key role in cancer progression and response to standard chemotherapy. Here, we provide a summary of the mechanisms by which the major cellular components of the ovarian cancer (OC) tumor microenvironment (TME) including cancer-associated fibroblasts (CAFs), myeloid, immune, endothelial, and mesothelial cells potentiate cancer progression. High-grade serous ovarian cancer (HGSOC) is characterized by a pro-inflammatory and angiogenic signature. This profile is correlated with clinical outcomes and can be a target for therapy...
August 10, 2018: Cancers
Mony Chenda Morisse, Stephanie Jouannet, Margarita Dominguez-Villar, Marc Sanson, Ahmed Idbaih
Glioblastoma (GBM) is the deadliest primary malignant central nervous system tumor with a median overall survival of 15 months despite a very intensive therapeutic regimen including maximal safe surgery, radiotherapy and chemotherapy. Therefore, GBM treatment still raises major biological and therapeutic challenges. Areas covered: One of the hallmarks of the GBM is its tumor microenvironment including tumor-associated macrophages (TAM). TAM, accounting for approximately 30% of the GBM bulk cell population, may explain, at least in part, the immunosuppressive features of GBMs...
August 13, 2018: Expert Review of Neurotherapeutics
Sai Han, Ying Wang, Xuejiao Shi, Liju Zong, Lu Liu, Juan Zhang, Qiuhong Qian, Jing Jin, Yana Ma, Baoxia Cui, Xingsheng Yang, Beihua Kong, Youzhong Zhang
Although persistent human papilloma virus (HPV) infection exerts a crucial influence on cervical carcinogenesis, other factors are also involved in its development, such as intraepithelial lesions and cervical cancer. B7-H3 and B7-H4, which have been reported to be co-regulatory ligands in the B7 family, had been found to be overexpressed in cervical cancer and correlated with adverse clinicopathological features and poor prognosis in our previous studies. In this study, we sought to explore the effects of B7-H3 and B7-H4 on the cervical microenvironment...
August 9, 2018: Experimental Cell Research
Sachin Kumar Deshmukh, Nikhil Tyagi, Mohammad Aslam Khan, Sanjeev Kumar Srivastava, Ahmed Al-Ghadhban, Kari Dugger, James Elliot Carter, Seema Singh, Ajay Pratap Singh
Chemotherapy-induced immunosuppression poses an additional challenge to its limited efficacy in pancreatic cancer (PC). Here we investigated the effect of gemcitabine on macrophages, which are the first line of immune-defense mechanisms. We observed an increased presence of macrophages in orthotopic human pancreatic tumor xenografts from mice treated with gemcitabine as compared to those from vehicle only-treated mice. Conditioned media from gemcitabine-treated PC cells (Gem-CM) promoted growth, migration and invasion of RAW264...
August 10, 2018: Scientific Reports
Angelika Terbuch, Juanita Lopez
Dramatic success in cancer immunotherapy has been achieved over the last decade with the introduction of checkpoint inhibitors, leading to response rates higher than with chemotherapy in certain cancer types. These responses are often restricted to cancers that have a high mutational burden and show pre-existing T-cell infiltrates. Despite extensive efforts, therapeutic vaccines have been mostly unsuccessful in the clinic. With the introduction of next generation sequencing, the identification of individual mutations is possible, enabling the production of personalized cancer vaccines...
August 9, 2018: Vaccines
Consuelo Buttigliero, Simona Allis, Marcello Tucci, Clizia Zichi, Gianmarco Leone, Rosario Francesco Di Stefano, Maria Grazia Ruo Redda, Umberto Ricardi, Giorgio Vittorio Scagliotti, Massimo Di Maio, Andrea Riccardo Filippi
In the last few years, immune checkpoint inhibitors have been extensively investigated in renal cell carcinoma and led to remarkable results. Radiation therapy may increase the activity of immune modulating agents through different mechanisms, priming the immune system, recruiting immune cells to the tumor environment, and altering the immunosuppressive effects of the tumor microenvironment. Preclinical studies reported increased loco-regional control when radiation is combined with immune-checkpoint blockade...
July 20, 2018: Cancer Treatment Reviews
Jibin Li, Jian Xu, Xiaofei Yan, Keer Jin, Wenya Li, Rui Zhang
BACKGROUND Limited efficacy of immune checkpoint blockades was observed in clinical trials in colorectal (CRC) patients, especially in the microsatellite-stable patients. Interleukin-6 (IL-6) is critical in modeling immune responses in cancers. However, the effects of targeting IL-6 in combination with immune checkpoint blockades is unknown in CRC. MATERIAL AND METHODS In the present study, we investigated the profile of IL-6 expression in tumor tissues of CRC patient and we established CRC mouse models with various IL-6 expression levels using CT26 cells and MC38 cells...
August 8, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Lin Hou, Qi Liu, Limei Shen, Yun Liu, Xueqiong Zhang, Fengqian Chen, Leaf Huang
Rationale: Tumor-associated fibroblasts (TAFs) play a critical role in the suppressive immune tumor microenvironment (TME), compromising the efficacy of immunotherapy. To overcome this therapeutic hurdle, we developed a nanoemulsion (NE) formulation to deliver fraxinellone (Frax), an anti-fibrotic medicine, to TAFs, as an approach to reverse immunosuppressive TME of desmoplastic melanoma. Methods: Frax NE was prepared by an ultrasonic emulsification method. The tumor inhibition effect was evaluated by immunofluorescence staining, masson trichrome staining and western blot analysis...
2018: Theranostics
Wenwen Zhang, Mengmeng Jiang, Jieying Chen, Rui Zhang, Yingnan Ye, Pengpeng Liu, Wenwen Yu, Jinpu Yu
Interleukin-6 (IL-6) is an important trigger for the expansion and recruitment of myeloid-derived suppressor cells (MDSCs), which are regarded to be major coordinators of the immunosuppressive tumor microenvironment. In this study, we constructed IL-6-knockdown breast cancer mice models to explore the molecular events involved in the IL-6-mediated effects on MDSC development. We defined a subset of early-stage MDSCs (e-MDSCs) with the phenotype of CD11b+ Gr-1- F4/80- MHCII- in IL-6 high-expressing 4T1 mice mammary carcinoma models, which were the precursors of CD11b+ Gr-1+ conventional MDSCs...
2018: Frontiers in Immunology
Andrea Botticelli, Bruna Cerbelli, Luana Lionetto, Ilaria Zizzari, Massimiliano Salati, Annalinda Pisano, Mazzuca Federica, Maurizio Simmaco, Marianna Nuti, Paolo Marchetti
BACKGROUND: Immune checkpoint inhibitors have revolutionized the treatment paradigm of highly lethal malignancies like advanced non-small cell lung cancer (NSCLC), demonstrating long-term tumour control and extended patient survival. Unfortunately, only 25-30% of patients experience a durable benefit, while the vast majority demonstrate primary or acquired resistance. Recently, indoleamine 2,3-dioxygenase (IDO) activity has been proposed as a possible mechanism of resistance to anti-PD-1 treatment leading to an immunosuppressive microenvironment...
August 6, 2018: Journal of Translational Medicine
Georges Herbein
Besides its well-described impact in immunosuppressed patients, the role of human cytomegalovirus (HCMV) in the pathogenesis of cancer has been more recently investigated. In cancer, HCMV could favor the progression and the spread of the tumor, a paradigm named oncomodulation. Although oncomodulation could account for part of the protumoral effect of HCMV, it might not explain the whole impact of HCMV infection on the tumor and the tumoral microenvironment. On the contrary cases have been reported where HCMV infection slows down the progression and the spread of the tumor...
August 3, 2018: Viruses
Valerio Leoni, Andrea Vannini, Valentina Gatta, Julie Rambaldi, Mara Sanapo, Catia Barboni, Anna Zaghini, Patrizia Nanni, Pier-Luigi Lollini, Costanza Casiraghi, Gabriella Campadelli-Fiume
Oncolytic herpes simplex viruses (oHSVs) showed efficacy in clinical trials and practice. Most of them gain cancer-specificity from deletions/mutations in genes that counteract the host response, and grow selectively in cancer cells defective in anti-viral response. Because of the deletions/mutations, they are frequently attenuated or over-attenuated. We developed next-generation oHSVs, which carry no deletion/mutation, gain cancer-specificity from specific retargeting to tumor cell receptors-e.g. HER2 (human epidermal growth factor receptor 2)-hence are fully-virulent in the targeted cancer cells...
August 6, 2018: PLoS Pathogens
Binghua Wang, Jingyi An, Huifang Zhang, Shudong Zhang, Huijuan Zhang, Lei Wang, Hongling Zhang, Zhenzhong Zhang
While immunotherapy has a tremendous clinical potential to combat cancer, immune responses generated by conventional cancer immunotherapy remain not enough to completely eliminate tumors, mainly due to the tumor's immunosuppressive microenvironment and heterogeneity of tumor immunogenicity. To improve antitumor immune responses and realize personalized immunotherapy, in this report, endogenous tumor antigens (ETAs) that dynamically present on tumor cells are transported to lymph nodes (LNs). Based on the hypothesis that nano Fe3 O4 (≈10 nm) could serve as the nanocarrier for transporting ETAs from the tumor to LNs, we wondrously find that Fe3 O4 has a tremendous potential to improve cancer immunotherapy, because of its excellent protein-captured efficiency and LNs-targeted ability...
August 6, 2018: Small
Roghayyeh Vakili-Ghartavol, Reza Mombeiny, Arash Salmaninejad, Seyed Mahdi Rezayat Sorkhabadi, Reza Faridi-Majidi, Mahmoud Reza Jaafari, Hamed Mirzaei
Tumor-associated macrophages (TAMs) are an important component of the leukocytic infiltrate of the tumor microenvironment. There is persuasive preclinical and clinical evidence that TAMs induce cancer inanition and malignant progression of primary tumors toward a metastatic state through a highly conserved and fundamental process known as epithelial-mesenchymal transition (EMT). Tumor cells undergoing EMT are distinguished by increased motility and invasiveness, which enable them to spread to distant sites and form metastases...
August 5, 2018: Journal of Cellular Physiology
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