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https://www.readbyqxmd.com/read/29133623/immu-140-a-novel-sn-38-antibody-drug-conjugate-targeting-hla-dr-mediates-dual-cytotoxic-effects-in-hematological-cancers-and-malignant-melanoma
#1
Thomas M Cardillo, Serengulam V Govindan, Maria B Zalath, Diane L Rossi, Yang Wang, Chien-Hsing Chang, David M Goldenberg
HLA-DR is a member of the MHC class II antigen family expressed on hematological and solid tumors.  Antibodies directed against HLA-DR have demonstrated some clinical success, but toxicities limited development.  IMMU-140 is an anti-HLA-DR antibody-drug conjugate comprised of the active metabolite of irinotecan, SN-38, conjugated to a humanized anti-HLA-DR IgG4 antibody (IMMU-114); the IgG4 naked antibody is devoid of immune functions. Our aim was to determine if SN-38, the metabolite of a drug not commonly used in hematopoietic cancers, would be effective and safe when targeted to HLA-DR-expressing tumors...
November 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29130994/enhancement-of-anti-leukemia-immunity-by-leukemia-derived-exosomes-via-downregulation-of-tgf-%C3%AE-1-expression
#2
Fang Huang, Jiangbo Wan, Weiwei Hu, Siguo Hao
BACKGROUND/AIMS: Minimal residual leukemia cells (MRLs) are difficult to eradicate through traditional treatment and therefore remain to be a major threat to the long-term survival of leukemia patients. Tumor-derived exosomes (TEXs), which carry tumor associated antigens (TAA), may be a potential cell-free tumor vaccine for the specific eradication of MRLs. However, TEXs are intended to be less immunogenic due to exosomal TGF-β1. To further optimize the efficacy of TEX-based vaccines, we investigated whether exosomes from TGF-β1 silenced leukemia cells (LEXTGF-β1si) had an increased potential to induce a specific antitumor effect compared with non-modified exosomes...
November 9, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29127275/allogeneic-stem-cell-transplantation-in-fully-mhc-matched-mauritian-cynomolgus-macaques-recapitulates-diverse-human-clinical-outcomes
#3
Benjamin J Burwitz, Helen L Wu, Shaheed Abdulhaqq, Christine Shriver-Munsch, Tonya Swanson, Alfred W Legasse, Katherine B Hammond, Stephanie L Junell, Jason S Reed, Benjamin N Bimber, Justin M Greene, Gabriela M Webb, Mina Northrup, Wolfram Laub, Paul Kievit, Rhonda MacAllister, Michael K Axthelm, Rebecca Ducore, Anne Lewis, Lois M A Colgin, Theodore Hobbs, Lauren D Martin, Betsy Ferguson, Charles R Thomas, Angela Panoskaltsis-Mortari, Gabrielle Meyers, Jeffrey J Stanton, Richard T Maziarz, Jonah B Sacha
Allogeneic hematopoietic stem cell transplantation (HSCT) is a critically important therapy for hematological malignancies, inborn errors of metabolism, and immunodeficiency disorders, yet complications such as graft-vs.-host disease (GvHD) limit survival. Development of anti-GvHD therapies that do not adversely affect susceptibility to infection or graft-vs.-tumor immunity are hampered by the lack of a physiologically relevant, preclinical model of allogeneic HSCT. Here we show a spectrum of diverse clinical HSCT outcomes including primary and secondary graft failure, lethal GvHD, and stable, disease-free full donor engraftment using reduced intensity conditioning and mobilized peripheral blood HSCT in unrelated, fully MHC-matched Mauritian-origin cynomolgus macaques...
November 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/29120508/synthesis-and-immunological-evaluation-of-a-multicomponent-cancer-vaccine-candidate-containing-a-long-muc1-glycopeptide
#4
Geert-Jan Boons, Nitin T Supekar, Vani Lakshminarayanan, Chantelle J Capicciotti, Anju Sirohiwal, Cathy S Madsen, Margreet A Wolfert, Peter A Cohen, Sandra J Gendler
A fully synthetic MUC1-based cancer vaccine has been designed and chemically synthesized that contains an endogenous helper T-epitope (MHC class II epitope). The vaccine elicited robust IgG titers that could neutralize cancer cells by antibody-dependent cell-mediated cytotoxicity (ADCC). It also activated cytotoxic T-lymphocytes and collectively the immunological data demonstrate engagement of helper T-cells in immune activation. A synthetic methodology was developed for a penta-glycosylated MUC1 glycopeptide and anti-sera of mice immunized by the new vaccine recognized such a structure...
November 9, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/29113227/low-dose-valproic-acid-with-low-dose-gemcitabine-augments-mhc-class-i-related-chain-a-b-expression-without-inducing-the-release-of-soluble-mhc-class-i-related-chain-a-b
#5
Tomoharu Miyashita, Kenji Miki, Takashi Kamigaki, Isamu Makino, Hidehiro Tajima, Shinichi Nakanuma, Hironori Hayashi, Hiroyuki Takamura, Sachio Fushida, Ali K Ahmed, John W Harmon, Tetsuo Ohta
To improve natural killer group 2 member D (NKG2D)-dependent cytotoxicity, the inhibition of cleavage and release of major histocompatibility complex class 1-related chain (MIC) molecules from the tumor surface are required. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, is able to induce cell-surface MICA/B on tumor cells. In the present study, the ability of VPA and gemcitabine (GEM) to upregulate MICA/B in pancreatic cancer cells was investigated, resulting in the inhibition of cleavage and release of MIC molecules from the tumor surface...
November 2017: Oncology Letters
https://www.readbyqxmd.com/read/29109146/peptide-splicing-by-the-proteasome
#6
Nathalie Vigneron, Violette Ferrari, Vincent Stroobant, Joanna Abi Habib, Benoit Van den Eynde
The proteasome is the major protease responsible for the production of antigenic peptides recognized by CD8+ cytolytic T cells (CTL). These peptides, generally 8-to-10 amino acid-long, are presented at the cell surface by major histocompatibility complex (MHC) class I molecules. Although for years, these peptides were believed to solely derive from linear fragments of proteins, this concept was challenged several years ago by the isolation of anti-tumor CTL that recognized spliced peptides, i.e. peptides composed of fragments originally distant in the parental protein...
November 6, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29107334/mhc-i-genotype-restricts-the-oncogenic-mutational-landscape
#7
Rachel Marty, Saghar Kaabinejadian, David Rossell, Michael J Slifker, Joris van de Haar, Hatice Billur Engin, Nicola de Prisco, Trey Ideker, William H Hildebrand, Joan Font-Burgada, Hannah Carter
MHC-I molecules expose the intracellular protein content on the cell surface, allowing T cells to detect foreign or mutated peptides. The combination of six MHC-I alleles each individual carries defines the sub-peptidome that can be effectively presented. We applied this concept to human cancer, hypothesizing that oncogenic mutations could arise in gaps in personal MHC-I presentation. To validate this hypothesis, we developed and applied a residue-centric patient presentation score to 9,176 cancer patients across 1,018 recurrent oncogenic mutations...
October 20, 2017: Cell
https://www.readbyqxmd.com/read/29106696/the-mechanisms-shaping-the-repertoire-of-cd4-foxp3-treg-cells
#8
REVIEW
Piotr Kraj, Leszek Ignatowicz
Regulatory T (Treg ) cells expressing Foxp3 transcription factor control homeostasis of the immune system, antigenic responses to commensal and pathogenic microbiota, and immune responses to self and tumor antigens. Treg cells differentiate in the thymus, (tTreg ) along with conventional CD4(+) T cells, in processes of positive and negative selection. Another class of Treg cells is generated in peripheral tissues (pTreg ) by inducing Foxp3 expression in conventional CD4(+) T cells in response to antigenic stimulation...
November 6, 2017: Immunology
https://www.readbyqxmd.com/read/29101157/the-mhc-i-genotype-influences-early-driver-events-in-cancer
#9
(no author information available yet)
The incidence of recurrent oncogenic alterations in a tumor is influenced by the MHC I genotype.
November 3, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29100935/immunomodulatory-effects-of-a-bioactive-fraction-of-strobilanthes-crispus-in-nmu-induced-rat-mammary-tumor-model
#10
Hassan Muhammad Yankuzo, Yusha'u Shu'aibu Baraya, Zulkarnain Mustapha, Kah Keng Wong, Nik Soriani Yaacob
ETHNOPHARMACOLOGICAL RELEVANCE: Strobilanthes crispus Blume is traditionally consumed among local Malay and indigenous communities for the treatment of cancer and other ailments such as gastrointestinal disorders, inflammatory wounds of snake bite and immune system activation amongst others. We previously demonstrated that a bioactive fraction of S. crispus leaves (F3) was cytotoxic to breast cancer cells in vitro and inhibited tumor growth in N-methyl-N-nitrosourea (NMU)-induced breast cancer rat model...
October 31, 2017: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/29093489/trem-1-promotes-intestinal-tumorigenesis
#11
Leslie Saurer, Daniel Zysset, Silvia Rihs, Lukas Mager, Matteo Gusberti, Cedric Simillion, Alessandro Lugli, Inti Zlobec, Philippe Krebs, Christoph Mueller
Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory innate immune responses. Increasing evidence suggests a role for TREM-1 not only in acute pathogen-induced reactions but also in chronic and non-infectious inflammatory disorders, including various types of cancer. Here, we demonstrate that genetic deficiency in Trem1 protects from colorectal cancer. In particular, Trem1 (-/-) mice exhibited reduced tumor numbers and load in an experimental model of inflammation-driven tumorigenesis...
November 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29089071/-whole-glucan-particle-promotes-the-maturation-of-tumor-educated-mouse-dendritic-cells-to-suppress-regulatory-t-cell-differentiation
#12
Yu Bai, Yongling Ning, Hong Zhou, Chunjian Qi
Objective To investigate the maturation and immune responses of tumor-educated dendritic cells (TEDCs) stimulated by whole glucan particle (WGP). Methods Mouse bone marrow-derived dendritic cells were generated by Flt3 ligand and co-cultured with interleukin 10 (IL-10) and transforming growth factor β (TGF-β) in vitro to induce TEDCs, and then stimulated by WGP for 2 days. CD4(+) FOXP3(+) T cells from the lymph nodes and spleens of OT-II mice were purified by magnetic-activated cell sorting, and then co-cultured with TEDCs in the presence of ovalbumin (OVA)...
September 2017: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
https://www.readbyqxmd.com/read/29079845/glycolipid-peptide-conjugate-vaccines-enhance-cd8-t-cell-responses-against-human-viral-proteins
#13
M Speir, A Authier-Hall, C R Brooks, K J Farrand, B J Compton, R J Anderson, A Heiser, T L Osmond, C W Tang, J A Berzofsky, M Terabe, G F Painter, I F Hermans, R Weinkove
An important goal of vaccination against viruses and virus-driven cancers is to elicit cytotoxic CD8(+) T cells specific for virus-derived peptides. CD8(+) T cell responses can be enhanced by engaging help from natural killer T (NKT) cells. We have produced synthetic vaccines that induce strong peptide-specific CD8(+) T cell responses in vivo by incorporating an NKT cell-activating glycolipid. Here we examine the effect of a glycolipid-peptide conjugate vaccine incorporating an NKT cell-activating glycolipid linked to an MHC class I-restricted peptide from a viral antigen in human peripheral blood mononuclear cells...
October 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29070816/resistance-to-checkpoint-blockade-therapy-through-inactivation-of-antigen-presentation
#14
Moshe Sade-Feldman, Yunxin J Jiao, Jonathan H Chen, Michael S Rooney, Michal Barzily-Rokni, Jean-Pierre Eliane, Stacey L Bjorgaard, Marc R Hammond, Hans Vitzthum, Shauna M Blackmon, Dennie T Frederick, Mehlika Hazar-Rethinam, Brandon A Nadres, Emily E Van Seventer, Sachet A Shukla, Keren Yizhak, John P Ray, Daniel Rosebrock, Dimitri Livitz, Viktor Adalsteinsson, Gad Getz, Lyn M Duncan, Bo Li, Ryan B Corcoran, Donald P Lawrence, Anat Stemmer-Rachamimov, Genevieve M Boland, Dan A Landau, Keith T Flaherty, Ryan J Sullivan, Nir Hacohen
Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29...
October 26, 2017: Nature Communications
https://www.readbyqxmd.com/read/29058602/the-crosstalk-between-autophagic-and-endo-exosomal-pathways-in-antigen-processing-for-mhc-presentation-in-anticancer-t-cell-immune-responses
#15
REVIEW
Liangshun You, Liping Mao, Juying Wei, Shenhe Jin, Chunmei Yang, Hui Liu, Li Zhu, Wenbin Qian
T cells recognize antigen fragments from proteolytic products that are presented to them in the form of peptides on major histocompatibility complex (MHC) molecules, which is crucial for the T cell to identify infected or transformed cells. Autophagy, a process that delivers cytoplasmic constituents for lysosomal degradation, has been observed to provide a substantial source of intra- and extracellular antigens for MHC presentation to T cells, which will impact the tumor-specific immune response. Meanwhile, extracellular components are transported to cytoplasm for the degradation/secretion process by the endo-/exosomal pathway and are thus involved in multiple physiological and pathological processes, including immune responses...
October 23, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29056908/upregulation-of-hla-class-i-expression-on-tumor-cells-by-the-anti-egfr-antibody-nimotuzumab
#16
Greta Garrido, Ailem Rabasa, Cristina Garrido, Lisset Chao, Federico Garrido, Ángel M García-Lora, Belinda Sánchez-Ramírez
Defining how epidermal growth factor receptor (EGFR)-targeting therapies influence the immune response is essential to increase their clinical efficacy. A growing emphasis is being placed on immune regulator genes that govern tumor - T cell interactions. Previous studies showed an increase in HLA class I cell surface expression in tumor cell lines treated with anti-EGFR agents. In particular, earlier studies of the anti-EGFR blocking antibody cetuximab, have suggested that increased tumor expression of HLA class I is associated with positive clinical response...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29054890/natural-killer-t-cell-immunotherapy-in-combination-with-chemotherapy-induced-immunogenic-cell-death-targets-metastatic-breast-cancer
#17
Simon Gebremeskel, Lynnea Lobert, Kaitlyn Tanner, Brynn Walker, Tora Oliphant, Livia E Clarke, Graham Dellaire, Brent Johnston
Natural killer T (NKT) cells are glycolipid-reactive lymphocytes that promote cancer control. In previous studies, NKT-cell activation improved survival and antitumor immunity in a post-surgical mouse model of metastatic breast cancer. Herein, we investigated whether NKT-cell activation could be combined with chemotherapeutic agents to augment therapeutic outcomes. Gemcitabine and cyclophosphamide analogs enhanced the potential immunogenicity of 4T1 mammary carcinoma cells by increasing the expression of antigen-presenting molecules (MHC-I, MHC-II, and CD1d) and promoting exposure or release of immunogenic cell death markers (calreticulin, HMGB1 and ATP)...
October 20, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29054272/insights-on-the-hla-binding-peptidome-in-cancer
#18
Douglas F Lake
The intracellular compartments for proteolytic antigen processing in tumor cells produce peptides that are presented by MHC molecules to T cells. But first, the ubiquitin ligase system tags defective, misfolded, aged, and unstable proteins for degradation through the proteasome. Ubiqitinated proteins are unfolded and fed into the barrel-shaped core of the proteasome where a collection of multiple different proteases cleave proteins into oligopeptides. After exiting the proteasome, these oligopeptides are either completely degraded into amino acids or trimmed at the N- and C-termini so that they bind to transporter associated with antigen processing (TAP)...
2017: Enzymes
https://www.readbyqxmd.com/read/29052750/impact-of-a-cd4-gene-haplotype-on-the-immune-response-in-minipigs
#19
Fany Blanc, Françoise Créchet, Nicolas Bruneau, Guillaume Piton, Jean-Jacques Leplat, Fabrice Andréoletti, Giorgia Egidy, Silvia Vincent-Naulleau, Emmanuelle Bourneuf
The cluster of differentiation 4 (CD4) molecule functions as a co-receptor for MHC class II binding to TCR in T helper cells. A CD4 epitope deficiency was identified in the swine MeLiM (melanoblastoma-bearing Libechov minipig) strain, a model for spontaneous cutaneous melanoma development and regression. Extensive sequencing revealed a high genetic variability of CD4 and the existence of several haplotypes segregating in MeLiM. Forty polymorphisms were identified in the coding sequence, out of which 20 correspond to non-synonymous variants and 10 are located in the 3'UTR of CD4 transcripts...
October 20, 2017: Immunogenetics
https://www.readbyqxmd.com/read/29048671/adoptive-immunotherapy-combined-with-fp-treatment-for-head-and-neck-cancer-an-in%C3%A2-vitro-study
#20
Mayako Nishio-Nagai, Susumu Suzuki, Kazuhiro Yoshikawa, Ryuzo Ueda, Yoshiaki Kazaoka
FP treatment, which combines 5-fluorouracil (5-FU) and cisplatin (CDDP) chemotherapy, is widely used for treatment of advanced head and neck cancer (HNC). It has been suggested that these drugs cause immunomodulation in the cancer microenvironment, for example, downregulation of immunosuppressive cells such as regulatory T-cells (Tregs) and myeloid-derived suppressive cells (MDSCs), activating dendritic cells (DCs), and upregulation of tumor antigens and major histocompatibility complex (MHC) molecules in cancer cells leads to enhancement of cancer immunity, which is important in cancer treatment, as well as providing a direct killing effect...
October 2, 2017: International Journal of Oncology
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