THE ROLE OF THE LECTIN BINDING PROTEIN, GALECTIN-3, ON REGULATING THE TUMOR SPECIFIC CD8 T CELL RESPONSE AFTER GM-CSF VACCINATION

Galectin-3;CD8 T cell;GM-CSF vaccination;LAG-3;plasmacytoid dendritic cells;Immunology

Kouo, Theodore SanderJaffee, Elizabeth M. ;

Johns Hopkins University

关键词: Galectin-3;    CD8 T cell;    GM-CSF vaccination;    LAG-3;    plasmacytoid dendritic cells;    Immunology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/37936/TedKouo_Thesis_Formatted.doc?sequence=3&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

BACKGROUND: Galectin-3 is a 31 kD carbohydrate-binding lectin that is over-expressed by many human malignancies.It also modulates T cell responses through a diverse array of mechanisms including induction of apoptosis, TCR cross linking in CD8+ T cells, and T cell receptor (TCR) down regulation in CD4+ T cells.It is also seen as a major regulator protein of the innate immune response.However, very few studies exist that describe its overall role in regulating a tumor-specific immune response in a tolerogenic host.METHODOLOGY/PRINCIPAL FINDINGS: We found that patients responding to a granulocyte-macrophage colony-stimulating factor (GM-CSF) secreting allogeneic pancreatic tumor vaccine developed post immunization antibody responses to galectin-3 on a proteomic screen.We used the HER-2/neu (neu-N) transgenic mouse model to study galectin-3 binding on adoptively transferred high avidity neu-specific CD8+ T cells derived from TCR transgenic mice.Here, we show that galectin-3 binds preferentially to activated antigen-committed CD8+ T cells only in the tumor microenvironment (TME).Galectin-3 deficient mice exhibit improved CD8+ T cell effector function and increased expression of several inflammatory genes when compared with wild type (WT) mice.We also show that galectin-3 complexes with LAG-3, and LAG-3 expression is necessary for galectin-3 mediated suppression of CD8+ T cells in vitro.Lastly, galectin-3 deficient mice have significantly elevated levels of circulating plasmacytoid dendritic cells (pDCs), which are superior to conventional dendritic cells (cDCs) in activating CD8+ T cells.CONCLUSION/SIGNIFICANCE: Binding of galectin-3 to cell surface glycoproteins on immune cells suppresses the pro-inflammatory immune response.Thus, inhibiting galectin-3 in conjunction with CD8+ T cell directed immunotherapies should enhance the tumor specific immune response.