TARGETING CD4 T CELLS WITH NANOTECHNOLOGY FOR ENHANCED CANCER IMMUNOTHERAPY

Helper (CD4+) T cells are pivotal to immune protection against a wide range of diseases and pathogens. They bridge the innate and adaptive immune systems, recruiting innate immune cells to sites of infection or disease and providing indispensable help signals to B cells and cytotoxic (CD8+) T cells. In addition to their helper roles, they perform a variety of direct therapeutic functions, secreting immunomodulatory cytokines or even directly mediating lysis of diseased cells. Nevertheless, a current lack of synthetic platforms for harnessing antigen-specific CD4+ T cell responses, hinders the widespread adoption of CD4+ T cell-based therapies. This thesis advances new nanotechnologies and methods to harness CD4+ T cells, toward a variety of immunological applications. The first contribution of this thesis is to demonstrate the manufacturing benefits of CD4+ T cells to enhance ex vivo production of CD8+ T cell therapies. While CD4+ T cells were initially believed to detract from production yields, I demonstrated through a series of depletion and addback studies that bystander CD4+ T cells increase the throughput, purity, and yield of antigen-specific CD8+ T cells during nanoparticle-based expansions. The second contribution of this thesis is to engineer a nanoparticle platform for ex vivo CD4+ T cell culture that mimics antigen presenting cells (APC) through display of murine major histocompatibility class II (MHC II) or human leukocyte antigen class II (HLA II) molecules. I demonstrated that MHC II and HLA II artificial APCs (aAPCs) expand cognate murine and human CD4+ T cells, respectively, which uniquely display cytotoxic activity. Moreover, I engineered novel combined MHC I/II aAPCs that simultaneously engage CD4+ and CD8+ T cells, thereby relaying help signals that enhance the function, memory formation, and antitumor activity of CD8+ T cells. These technologies facilitated discovery of important biophysical parameters for CD4+ T cell binding, activation, and enrichment, specific cues that induce cytotoxic CD4+ T cells, and key helper signals provided by CD4+ T cells to CD8+ T cells