Modulation of T Cell Antitumor Immunity Through Acetylcholine Signaling

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dc.contributor.authorGuagliano, Ryan
dc.contributor.supervisorLum, Julian J.
dc.date.accessioned2023-08-22T23:59:56Z
dc.date.copyright2023en_US
dc.date.issued2023-08-22
dc.degree.departmentDepartment of Biochemistry and Microbiologyen_US
dc.degree.levelMaster of Science M.Sc.en_US
dc.description.abstractImmunotherapies such as chimeric antigen receptor T cells (CAR-T cells) have shown promising results in many cancer patients but are still limited in solid cancers. Solid cancers contain immunosuppressive factors in the tumor microenvironment (TME), such as hypoxia and glucose deprivation. Antigen heterogeneity reduces therapy effectiveness in many cancers as CAR-T receptors need to recognize specific antigen that may be absent. This thesis investigates the function of a prominent TME metabolite: the neurotransmitter acetylcholine (ACh). Primary data from our lab shows that T cells infiltrating the TME have elevated ACh. Recent publications show ACh signaling influences mouse T cells to express a transcription factor FoxP3, a marker for regulatory T cells (Tregs) that contribute to the suppressive TME. However, there is little progress in testing the impact of these ACh-stimulated T cells’ anticancer functions. Data from my thesis indicates that folate receptor alpha (FRα) CAR-T cell antitumor effector function is enhanced, rather than suppressed by ACh. ACh promotes transient expression of human FOXP3 in activated proinflammatory effector T cells (Teffs) expressing interferon gamma (IFN-γ). My results identify the alpha 7 nicotinic acetylcholine receptor (α7 nAChR) is involved in increasing FOXP3, but not IFN-γ expression in human T cells and the enzyme choline acetyltransferase (ChAT) which catalyzes the rate-limiting step in the synthesis of ACh, is required for self-regulation of FOXP3 and the activation marker CD25 following activation. Helios, a transcription factor and Treg stability marker is likewise transiently expressed by active Teffs and only FOXP3+/Helios-, IFN-γ+ Teffs proliferate throughout expansion. Taken together, my results indicate that ACh signaling in vitro enhances T cell activation and differentiation into antitumor Teffs, and this could be used for novel methods to increase the efficiency of current solid cancer therapies through manipulation of FOXP3 and/or IFN-γ.en_US
dc.description.embargo2024-08-09
dc.description.scholarlevelGraduateen_US
dc.identifier.urihttp://hdl.handle.net/1828/15283
dc.languageEnglisheng
dc.language.isoenen_US
dc.rightsAvailable to the World Wide Weben_US
dc.subjectbiochemistryen_US
dc.subjectcanceren_US
dc.subjectcancer biologyen_US
dc.subjectCAR-t cellsen_US
dc.subjectt cellsen_US
dc.subjectacetylcholineen_US
dc.subjectflow cytometryen_US
dc.subjectimmunologyen_US
dc.subjectinterferon gammaen_US
dc.subjectIFN-gen_US
dc.subjectfoxp3en_US
dc.subjectregulatory T cellen_US
dc.subjecteffector t cellsen_US
dc.subjectteffen_US
dc.subjecttregen_US
dc.subjectluciferaseen_US
dc.subjectELISAen_US
dc.subjectcytotoxicityen_US
dc.titleModulation of T Cell Antitumor Immunity Through Acetylcholine Signalingen_US
dc.typeThesisen_US

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