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Regulation of Anti-tumor Immunity in Colorectal Cancer by Interaction of Exosome Immune Complexes with Fc gamma Receptors

  • Author / Creator
    McNamara, Allison M
  • Targeted therapy is difficult for colorectal cancer (CRC) due to lack of conserved tumor associated antigens (TAA). Immunotherapies for CRC directed at TAA that can overcome intestinal tolerance need to be developed to improve survival of CRC patients. Exosomes are extracellular vesicles secreted by CRC cells that carry TAAs and display unique surface phospholipids (PPL). Although exosomes represent an ideal delivery vehicle for TAA into the immune system, most evidence indicates that they are immunosuppressive. However, the surface PPL on exosomes can be bound by PPL-specific immunoglobulin G (IgG) to generate immune complexes (IC). We hypothesized that engagement of the Fc region of the IC with activating IgG-binding Fc receptors on dendritic cells (DC) and macrophages could prime sufficient CD8+ T-cell anti-tumor immunity and release of immune-enhancing cytokines to overcome immunosuppression. To test this, DC or macrophages were stimulated with exosomes from MC38 murine CRC cells complexed or not with anti-PPL IgG. Greater of activation of STAT1 along with expression of inflammatory genes IL-1B, IL-6, COX-2 and IL-12 were observed in DC and macrophages stimulated with IC than with exosomes alone. To verify that this was Fc receptor-dependent, we co-cultured CD8+ T cells with DC exposed to IC or exosomes alone in the presence or absence of Fc receptor-blocking antibodies. IC led to greater T cell activation than exosomes alone only when they could bind Fc receptors. In mice bearing an MC38 tumor transfected with OVA and given OVA-specific OT-I T cells, splenic DC upregulated the activation marker CD86 when treated with IC but not exosomes alone. No difference in IFN gamma expression by tumor infiltrating T cells was detected in these mice, however splenic OVA-specific T cells exhibited greater expression of IFN gamma following IC treatment. This suggests that exosome IC can prime CD8+ T cells under ideal conditions but not in the suppressive CRC environment. Further investigation of anti-PPL will allow us to understand whether this strategy could help increase anti-tumor immunity and survival in CRC patients.

  • Subjects / Keywords
  • Graduation date
    Spring 2019
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/r3-5838-dr52
  • License
    Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.