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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

A NOVEL APPROACH TO SELECTIVELY TARGET AND REPROGRAM REGULATORY T CELLS IN THE TUMOR MICROENVIRONMENT

Rami Akram Alfar (13949481) 13 October 2022 (has links)
<p> Although immune checkpoint inhibitors block one mechanism of regulatory T cell (Treg) immunosuppression, no drug has been designed to inhibit all immunosuppressive activities of Tregs. We describe here a mechanism for manipulating Treg function in a tumor microenvironment without altering their properties in healthy tissues. For this purpose, we first identify a small molecule that binds specifically to Tregs in tumors but not in healthy tissues. We then exploit this binder to deliver an attached imaging agent or an immune activator specifically into tumor-resident Tregs. Analysis of the resulting tumors demonstrates that targeting of a Toll-like receptor 7 agonist to tumor Tregs inhibits their expression of FOXP3, PD-1, CTLA4, and HELIOS, resulting in 40-80% reduction in tumor growth and repolarization of other tumor-infiltrating immune cells to more inflammatory phenotypes. Since Tregs comprise <1% of cells in the tumor masses examined, these data argue that Tregs exert a disproportionately large effect on tumor immunity. The data also demonstrate that the immunosuppressive properties of Tregs can be manipulated without altering their properties in healthy tissues.</p>

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