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Kelly D Moynihan, Cary F Opel, Gregory L Szeto, Alice Tzeng, Eric F Zhu, Jesse M Engreitz, Robert T Williams, Kavya Rakhra, Michael H Zhang, Adrienne M Rothschilds, Sudha Kumari, Ryan L Kelly, Byron H Kwan, Wuhbet Abraham, Kevin Hu, Naveen K Mehta, Monique J Kauke, Heikyung Suh, Jennifer R Cochran, Douglas A Lauffenburger, K Dane Wittrup, Darrell J Irvine
Checkpoint blockade with antibodies specific for cytotoxic T lymphocyte-associated protein (CTLA)-4 or programmed cell death 1 (PDCD1; also known as PD-1) elicits durable tumor regression in metastatic cancer, but these dramatic responses are confined to a minority of patients. This suboptimal outcome is probably due in part to the complex network of immunosuppressive pathways present in advanced tumors, which are unlikely to be overcome by intervention at a single signaling checkpoint. Here we describe a combination immunotherapy that recruits a variety of innate and adaptive immune cells to eliminate large tumor burdens in syngeneic tumor models and a genetically engineered mouse model of melanoma; to our knowledge tumors of this size have not previously been curable by treatments relying on endogenous immunity...
October 24, 2016: Nature Medicine
Emilie Duvallet, Mathilde Boulpicante, Takahiro Yamazaki, Chrysoula Daskalogianni, Rodrigo Prado Martins, Sonia Baconnais, Bénédicte Manoury, Robin Fahraeus, Sébastien Apcher
Cellular immune reactions against non-self-epitopes require activation of cytotoxic CD8(+) T-cells via cross-presentation of MHC class I-restricted peptides by professional antigen presenting cells (pAPCs), with the consequent detection and elimination of cells expressing the same antigens via the endogenous (direct) pathway. The source of peptides for the endogenous pathway is constituted of alternative mRNA translation products; however, it is still unclear which source of peptides is used for cross-presentation...
2016: Oncoimmunology
Pavel Hanč, Oliver Schulz, Hanna Fischbach, Stephen R Martin, Svend Kjær, Caetano Reis E Sousa
DNGR-1 is receptor expressed by certain dendritic cell (DC) subsets and by DC precursors in mouse. It possesses a C-type lectin-like domain (CTLD) followed by a poorly characterized neck region coupled to a transmembrane region and short intracellular tail. The CTLD of DNGR-1 binds F-actin exposed by dead cell corpses and causes the receptor to signal and potentiate cross-presentation of dead cell-associated antigens by DCs. Here, we describe a conformational change that occurs in the neck region of DNGR-1 in a pH- and ionic strength-dependent manner and that controls cross-presentation of dead cell-associated antigens...
October 17, 2016: EMBO Journal
Alexander K Andrianov, Alexander Marin, Thomas R Fuerst
Two macromolecular immunoadjuvants - poly[di(carboxylatophenoxy)phosphazene], PCPP and poly[di(carboxylatoethylphenoxy)phosphazene], PCEP have been investigated for their molecular interactions with model and bio-pharmaceutically important proteins in solutions, as well as for their TLR stimulatory effects and pH-dependent membrane disruptive activity in cellular assays. Solution interactions between polyphosphazenes and proteins, including antigens and soluble immune receptor proteins, have been studied using Asymmetric Flow Field Flow Fractionation (AF4) and Dynamic Light Scattering (DLS) at near physiological conditions - phosphate buffered saline, pH 7...
October 17, 2016: Biomacromolecules
Manglio Rizzo, Laura Alaniz, Guillermo D Mazzolini
In recent years immunotherapy has revolutionized the treatment of patients with advanced cancer. The increased knowledge in the tumor immune-biology has allowed developing rational treatments by manipulation of the immune system with significant clinical impact. This rapid development has significantly changed the prognosis of many tumors without treatment options up to date. Other strategies have explored the use of therapeutic vaccines based on dendritic cells (DC) by inducing antitumor immunity. DC are cells of hematopoietic origin, constitutively expressing molecules capable to present antigens, that are functionally the most potent inducers of the activation and proliferation of antigen specific T lymphocytes...
2016: Medicina
Kamal El Bissati, Aziz A Chentoufi, Paulette A Krishack, Ying Zhou, Stuart Woods, Jitender P Dubey, Lo Vang, Joseph Lykins, Kate E Broderick, Ernest Mui, Yasuhiro Suzuki, Qila Sa, Stephanie Bi, Nestor Cardona, Shiv K Verma, Laura Frazeck, Catherine A Reardon, John Sidney, Jeff Alexander, Alessandro Sette, Tom Vedvick, Chris Fox, Jeffrey A Guderian, Steven Reed, Craig W Roberts, Rima McLeod
We created and tested multi-epitope DNA or protein vaccines with TLR4 ligand emulsion adjuvant (gluco glucopyranosyl lipid adjuvant in a stable emulsion [GLA-SE]) for their ability to protect against Toxoplasma gondii in HLA transgenic mice. Our constructs each included 5 of our best down-selected CD8(+) T cell-eliciting epitopes, a universal CD4(+) helper T lymphocyte epitope (PADRE), and a secretory signal, all arranged for optimal MHC-I presentation. Their capacity to elicit immune and protective responses was studied using immunization of HLA-A*11:01 transgenic mice...
September 22, 2016: JCI Insight
Myriam Lawand, Anastasia Abramova, Valérie Manceau, Sebastian Springer, Peter van Endert
Cross-presentation of phagocytosed Ags by MHC class I (MHC-I) molecules is thought to involve transport of cytosolic peptides into dendritic cell phagosomes, mediated by TAP transporters recruited from the endoplasmic reticulum. However, because pure and tightly sealed phagosomes are difficult to obtain, direct evidence for peptide transport into phagosomes has remained limited. Moreover, the parameters determining peptide uptake by, and survival in, phagosomes remain little characterized. In this study, we monitored peptide import into phagosomes by flow cytometry using two types of fluorescent reporter peptides, one of which directly bound to intraphagosomal beads...
September 23, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Viswa Teja Colluru, Douglas G McNeel
In spite of remarkable preclinical efficacy, DNA vaccination has demonstrated low immunogenicity in humans. While efforts have focused on increasing cross-presentation of DNA-encoded antigens, efforts to increase DNA vaccine immunogenicity by targeting direct presentation have remained mostly unexplored. In these studies, we compared the ability of different APCs to present antigen to T cells after simple co-culture with plasmid DNA. We found that human primary peripheral B lymphocytes, and not monocytes or in vitro derived dendritic cells (DCs), were able to efficiently encode antigen mRNA and expand cognate tumor antigen-specific CD8 T cells ex vivo...
September 21, 2016: Oncotarget
Florian Wiede, Faruk Sacirbegovic, Yew Ann Leong, Di Yu, Tony Tiganis
Non-coding single nucleotide polymorphisms that repress PTPN2 expression have been linked with the development of type 1 diabetes, rheumatoid arthritis and Crohn's disease. PTPN2 attenuates CD8(+) T cell responses to self and prevents overt autoreactivity in the context of T cell homeostasis and antigen cross-presentation. The role of PTPN2 in other immune subsets in the development of autoimmunity remains unclear. Here we show that the inducible deletion of PTPN2 in hematopoietic compartment of adult non-autoimmune prone mice results in systemic inflammation and autoimmunity...
September 19, 2016: Journal of Autoimmunity
Masahiro Azuma, Yohei Takeda, Hiroko Nakajima, Haruo Sugiyama, Takashi Ebihara, Hiroyuki Oshiumi, Misako Matsumoto, Tsukasa Seya
Successful cancer immunotherapy necessitates T cell proliferation and infiltration into tumor without exhaustion, a process closely links optimal maturation of dendritic cells (DC), and adjuvant promotes this process as an essential prerequisite. Poly(I:C) has contributed to adjuvant immunotherapy that evokes an antitumor response through the Toll-loke receptor 3 (TLR3)/TICAM-1 pathway in DC. However, the mechanism whereby Poly(I:C) acts on DC for T cell proliferation and migration remains undetermined. Subcutaneous injection of Poly(I:C) regressed implant tumors (WT1-C1498 or OVA-EG7) in C57BL/6 mice, which coincided with tumor-infiltration of CD8(+) T cells...
August 2016: Oncoimmunology
Paraskevi Kokkala, Anastasia Mpakali, Francois-Xavier Mauvais, Athanasios Papakyriakou, Ira Daskalaki, Ioanna Petropoulou, Sofia Kavvalou, Mirto Papathanasopoulou, Stefanos Agrotis, Theodora-Markisia Fonsou, Peter van Endert, Efstratios Stratikos, Dimitris Georgiadis
The oxytocinase subfamily of M1 aminopeptidases, consisting of ER aminopeptidase 1 (ERAP1), ER aminopeptidase 2 (ERAP2), and insulin-regulated aminopeptidase (IRAP), plays critical roles in the generation of antigenic peptides and indirectly regulates human adaptive immune responses. We have previously demonstrated that phosphinic pseudotripeptides can constitute potent inhibitors of this group of enzymes. In this study, we used synthetic methodologies able to furnish a series of stereochemically defined phosphinic pseudotripeptides and demonstrate that side chains at P1' and P2' positions are critical determinants in driving potency and selectivity...
October 13, 2016: Journal of Medicinal Chemistry
T Sun, O L Rojas, C Li, L A Ward, D J Philpott, J L Gommerman
Although we know a great deal about which types of dendritic cells (DCs) promote T-cell priming in the periphery, less is known about which DC subset(s) provoke antiviral responses within the gut. Here we report that conventional Zbtb46-dependent DCs were critically required for antiviral CD8(+) T-cell responses against rotavirus (RV), the major cause of childhood gastroenteritis worldwide. Furthermore, we found that in adult mice, Batf3-dependent DCs were required for generating optimal RV-specific CD8(+) T-cell responses...
September 7, 2016: Mucosal Immunology
Signe Tandrup Schmidt, Swapnil Khadke, Karen Smith Korsholm, Yvonne Perrie, Thomas Rades, Peter Andersen, Camilla Foged, Dennis Christensen
A prerequisite for vaccine-mediated induction of CD8(+) T-cell responses is the targeting of dendritic cell (DC) subsets specifically capable of cross-presenting antigen epitopes to CD8(+) T cells. Administration of a number of cationic adjuvants via the intraperitoneal (i.p.) route has been shown to result in strong CD8(+) T-cell responses, whereas immunization via e.g. the intramuscular (i.m.) or subcutaneous (s.c.) routes often stimulate weak CD8(+) T-cell responses. The hypothesis for this is that self-drainage of the adjuvant/antigen to the lymphoid organs, which takes place upon i...
October 10, 2016: Journal of Controlled Release: Official Journal of the Controlled Release Society
Tim J A Hutten, Soley Thordardottir, Hanny Fredrix, Lisanne Janssen, Rob Woestenenk, Jurjen Tel, Ben Joosten, Alessandra Cambi, Mirjam H M Heemskerk, Gerben M Franssen, Otto C Boerman, Lex B H Bakker, Joop H Jansen, Nicolaas Schaap, Harry Dolstra, Willemijn Hobo
Potent immunotherapies are urgently needed to boost antitumor immunity and control disease in cancer patients. As dendritic cells (DCs) are the most powerful APCs, they are an attractive means to reinvigorate T cell responses. An appealing strategy to use the effective Ag processing and presentation machinery, T cell stimulation and cross-talk capacity of natural DC subsets is in vivo tumor Ag delivery. In this context, endocytic C-type lectin receptors are attractive targeting molecules. In this study, we investigated whether CLEC12A efficiently delivers tumor Ags into human DC subsets, facilitating effective induction of CD4(+) and CD8(+) T cell responses...
October 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Chintan H Kapadia, Shaomin Tian, Jillian L Perry, J Christopher Luft, Joseph M DeSimone
Educating our immune system via vaccination is an attractive approach to combat infectious diseases. Eliciting antigen specific cytotoxic T cells (CTLs), CD8(+) effector T cells, is essential in controlling intracellular infectious diseases such as influenza (Flu), tuberculosis (TB), hepatitis, and HIV/AIDS, as well as tumors. However, vaccination utilizing subunit peptides to elicit a potent CD8(+) T cell response with antigenic peptides is typically ineffective due to poor immunogenicity. Here we have engineered a reduction sensitive nanoparticle (NP) based subunit vaccine for intracellular delivery of an antigenic peptide and immunostimulatory adjuvant...
October 3, 2016: Molecular Pharmaceutics
Yuanyuan Ding, Zhenhong Guo, Yiqi Liu, Xia Li, Qian Zhang, Xiongfei Xu, Yan Gu, Yi Zhang, Dezhi Zhao, Xuetao Cao
CD8α(+) dendritic cells (DCs) are specialized at cross-presenting extracellular antigens on major histocompatibility complex (MHC) class I molecules to initiate cytotoxic T lymphocyte (CTL) responses; however, details of the mechanisms that regulate cross-presentation remain unknown. We found lower expression of the lectin family member Siglec-G in CD8α(+) DCs, and Siglec-G deficient (Siglecg(-/-)) mice generated more antigen-specific CTLs to inhibit intracellular bacterial infection and tumor growth. MHC class I-peptide complexes were more abundant on Siglecg(-/-) CD8α(+) DCs than on Siglecg(+/+) CD8α(+) DCs...
October 2016: Nature Immunology
Chanyoung Song, Young-Woock Noh, Yong Taik Lim
Effective induction of an antigen-specific cytotoxic T lymphocyte (CTL) immune response is one of the key goals of cancer immunotherapy. We report the design and fabrication of polyethylenimine (PEI)-coated polymer nanoparticles (NPs) as efficient antigen-delivery carriers that can induce antigen cross-presentation and a strong CTL response. After synthesis of poly(d,l-lactide-co-glycolide) (PLGA) NPs containing ovalbumin (OVA) by the double-emulsion solvent-evaporation method, cationic-charged PLGA NPs were generated by coating them with PEI...
2016: International Journal of Nanomedicine
Lei Qin, Donye Dominguez, Siqi Chen, Jie Fan, Alan Long, Minghui Zhang, Deyu Fang, Yi Zhang, Timothy M Kuzel, Bin Zhang
Emerging studies suggest that dominant peripheral tolerance is a major mechanism of immune escape in disseminated leukemia. Using an established murine acute myeloid leukemia (AML) model, we here show that systemic administration of recombinant IL-33 dramatically inhibits the leukemia growth and prolongs the survival of leukemia-bearing mice in a CD8+ T cell dependent manner. Exogenous IL-33 treatment enhanced anti-leukemia activity by increasing the expansion and IFN-γ production of leukemia-reactive CD8+ T cells...
August 10, 2016: Oncotarget
Chiraz Hamimi, Annie David, Pierre Versmisse, Laurence Weiss, Timothée Bruel, David Zucman, Victor Appay, Arnaud Moris, Marie-Noëlle Ungeheuer, Caroline Lascoux-Combe, Françoise Barré-Sinoussi, Michaela Muller-Trutwin, Faroudy Boufassa, Olivier Lambotte, Gianfranco Pancino, Asier Sáez-Cirión
HIV controllers (HICs), rare HIV-1 infected individuals able to control viral replication without antiretroviral therapy, are characterized by an efficient polyfunctional and cytolytic HIV-specific CD8+ T cell response. The mechanisms underlying the induction and maintenance of such response in many HICs despite controlled viremia are not clear. Dendritic cells play a crucial role in the generation and reactivation of T cell responses but scarce information is available on those cells in HICs. We found that monocyte derived dendritic cells (MDDCs) from HICs are less permissive to HIV-1 infection than cells from healthy donors...
2016: PloS One
Raghvendra M Srivastava, Sumita Trivedi, Fernando Concha-Benavente, Sandra P Gibson, Carly Reeder, Soldano Ferrone, Robert L Ferris
PURPOSE: Cetuximab, an EGFR-specific antibody (mAb), modestly improves clinical outcome in head and neck cancer (HNC) patients. Cetuximab mediates natural killer (NK) cell:dendritic cell (DC) cross-talk by cross-linking FcγRIIIa, which is important for inducing anti-tumor cellular immunity. Cetuximab activated NK cells upregulate the costimulatory receptor CD137 (4-1BB) which, when triggered by agonistic mAb urelumab, might enhance NK cell functions, to promote T cell based immunity...
August 5, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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