Delivery of sting agonist using lipid nanoparticles and discovery of anti-TIGIT peptides for cancer therapy
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Over the past decades, cancer treatment has significantly advanced with the approval of new therapeutic entities aimed at treating this disease. However, these advancements have not universally benefitted all patients or different cancers due to the complexity of the tumor microenvironment found in these malignancies. Therefore, it has become crucial to understand the molecular and cellular mechanisms that cancer cells use to evade the immune system of their hosts in order to discover effective therapeutic interventions. Tumors can be classified based on their immunogenicity into two types: cold and hot tumors. Cold tumors like pancreatic cancer, glioblastoma, prostate cancer, and ovarian cancer exhibit a high number of immune suppressive cells including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSC), and cancer-associated fibroblasts (CAFs). Additionally, they often lack significant infiltration of immune cells like T cells. On the other hand, hot tumors contain T cells and other immune cells within the tumor microenvironment. However, despite the presence of these immune cells, cancer cells utilize various mechanisms to render the immune cells, especially T cells, dysfunctional, thereby evading the immune system. One significant mechanism involves immune checkpoints, where cancer cells manipulate the interaction between a receptor on T cells and a ligand on cancer cells. This manipulation often involves the cancer cells overexpressing their specific ligands, leading to a phenomenon where T cells become exhausted and unable to effectively eliminate tumor cells. Cold tumors can be treated by converting them into hot tumors and then removing the brakes by inhibiting the receptor-ligand interaction. This dissertation focuses on two main research objectives related to the interventions mentioned above. The first research aims to deliver a STING agonist into a cold tumor using lipid nanoparticles. This delivery is intended to provoke an immune response that leads to the elimination of tumor cells. STING pathway agonism has shown promise in innate immune signaling to tune the tumor microenvironment toward an immunogenic phenotype by promoting immune cell infiltration, especially CD8+ T cells, in various types of cancer. The second research involves the discovery of anti-TIGIT cyclic peptides using phage biopanning to block the interaction between the receptor TIGIT and its high-affinity ligand, CD155. In clinical studies, inhibiting this pathway within the adaptive immune system has demonstrated the ability to reverse the exhaustion of T- and NK cells, thereby restoring their functional ability to elicit cytotoxic activity against tumor cells. Chapter 1 introduces the dissertation research, presenting the statement of problems and outlining the research objectives. Chapter 2 provides an in-depth literature review on pancreatic cancer, the STING-2’3’-cGAMP pathway activation, and TIGIT-CD155 checkpoint inhibition for cancer immunotherapy. Chapter 3 involves the development and characterization of 2’3 cGAMP lipid nanoparticles (cGAMP-LNP) using various in-vitro and in-vivo techniques. These biodegradable cGAMP-LNP were prepared by encapsulating 2’3' -cGAMP within a lipid-based system containing an ionizable lipid, LHHK, and co-lipids. The cGAMP-LNP were found to have higher cellular uptake, improved IRF activation, and endosomolytic activity compared to free cGAMP in various cell-based assays. The cGAMP-LNP demonstrated significant inhibition of pancreatic cancer growth in a mouse model. Furthermore, these LNPs displayed a good safety profile in both in-vitro and in-vivo testing. These results suggest that cGAMP-LNP is a promising therapeutic entity for cold tumors like pancreatic cancer. In Chapter 4, the dissertation illustrates the discovery of anti-TIGIT cyclic peptides using the phage display technique. A unique cyclic peptide library developed in our laboratory was utilized to identify cyclic peptides using a solution-based biopanning procedure. These peptides were selected for their ability to bind to the TIGIT protein and block the TIGIT-CD155 interaction. The blocking efficiency was analyzed using an in-vitro protein-based assay, and two peptides, CSCP-7, and CSCP-16, showed the highest blocking of TIGIT-CD155 interaction. Moreover, alanine scanning revealed the amino acids responsible for the blocking activity of the CSCP-16 peptide.
Table of Contents
Introduction -- Literature review -- Delivery of a sting agonist using lipid nanoparticles inhibits pancreatic cancer growth -- Discovery of anti-tigit cyclic peptides blocking the tigit-CD155 interaction -- Summary and conclusion
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Ph.D. (Doctor of Philosophy)