| Popis: |
The effector function of cytotoxic lymphocytes (CTLs) is precisely managed through TCR MHC engagement, co-stimulatory axis as well as co-inhibitory pathways. Due to the deprived environment in a tumor and persistent antigen stimulation, CTLs lose their ability to effectively kill malignant cells, rendering them dysfunctional and exhausted. One reason is because they upregulate co-inhibitory surface proteins that reduce the activation of the T cell and therefore its effector function. Immune checkpoint inhibitors (ICI) are a class of immunotherapies targeting immune checkpoint proteins with the intention of restoring anti-tumor immunity. Anti-CTLA4 was the first ICI to gain FDA approval, and anti-PD1 is the second, both have been investigated heavily to optimize the benefit to the patient. Due to the non-redundant, yet sometimes convergent, nature of the ICs pathway it has been shown that combination therapies are providing additional benefit to the patients. Therefore, it is imperative that we continue to fund and study emerging checkpoint proteins stand alone and in combination treatment with other ICIs or other immunotherapies. This thesis examines VISTA, an emerging immune checkpoint protein, on CD8+ T cells in the tumor. We make the case that genetic deletion of VISTA allows for superior T cell function and less exhaustion with a more diverse T cell receptor (TCR) repertoire and more tumor control with combination therapy. VISTA, without any signaling domains, is largely thought of as a ligand. We sought to understand how deleting a ligand can have such potent T cell intrinsic effects, so we explored potential CIS binding receptors in the tumor. We discovered that VISTA binds another immune checkpoint receptor (ICR) and has measurable TCR and AKT signaling pathway suppression via the ICR’s signaling cytoplasmic tail. This thesis helps to bridge the knowledge gap of whether VISTA has receptor properties and T cell intrinsic effects in the tumor. |
