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Improved cytotoxic T-lymphocyte immune responses to a tumor antigen by vaccines co-expressing the SLAM-associated adaptor EAT-2.

Abstract
The signaling lymphocytic activation molecule-associated adaptor Ewing's sarcoma's-activated transcript 2 (EAT-2) is primarily expressed in dendritic cells, macrophages and natural killer cells. Including EAT-2 in a vaccination regimen enhanced innate and adaptive immune responses toward pathogen-derived antigens, even in the face of pre-existing vaccine immunity. Herein, we investigate whether co-vaccinations with two recombinant Ad5 (rAd5) vectors, one expressing the carcinoembryonic antigen (CEA) and one expressing EAT-2, can induce more potent CEA-specific cytotoxic T lymphocyte (CTL) and antitumor activity in the therapeutic CEA-expressing MC-38 tumor model. Our results suggest that inclusion of EAT-2 significantly alters the kinetics of Th1-biasing proinflammatory cytokine and chemokine responses, and enhances anti-CEA-specific CTL responses. As a result, rAd5-EAT2-augmented rAd5-CEA vaccinations are more efficient in eliminating CEA-expressing target cells as measured by an in vivo CTL assay. Administration of rAd5-EAT2 vaccines also reduced the rate of growth of MC-38 tumor growth in vivo. Also, an increase in MC-38 tumor cell apoptosis (as measured by hematoxylin and eosin staining, active caspase-3 and granzyme B levels within the tumors) was observed. These data provide evidence that more efficient, CEA-specific effector T cells are generated by rAd5 vaccines expressing CEA, when augmented by rAd5 vaccines expressing EAT-2, and this regimen may be a promising approach for cancer immunotherapy in general.
AuthorsY A Aldhamen, S S Seregin, Y A Kousa, D P W Rastall, D M Appledorn, S Godbehere, B C Schutte, A Amalfitano
JournalCancer gene therapy (Cancer Gene Ther) Vol. 20 Issue 10 Pg. 564-75 (Oct 2013) ISSN: 1476-5500 [Electronic] England
PMID23949283 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Adaptor Proteins, Signal Transducing
  • Antigens, CD
  • Cancer Vaccines
  • Carcinoembryonic Antigen
  • Receptors, Cell Surface
  • Sh2d1b1 protein, mouse
  • Signaling Lymphocytic Activation Molecule Family Member 1
Topics
  • Adaptor Proteins, Signal Transducing (biosynthesis, genetics, immunology)
  • Adenoviridae (genetics)
  • Animals
  • Antigens, CD (genetics, immunology)
  • Cancer Vaccines (genetics, immunology, pharmacology)
  • Carcinoembryonic Antigen (biosynthesis, genetics, immunology)
  • Genetic Vectors (genetics)
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Random Allocation
  • Receptors, Cell Surface (genetics, immunology)
  • Signaling Lymphocytic Activation Molecule Family Member 1
  • T-Lymphocytes, Cytotoxic (drug effects, immunology)

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