The Mechanism of cGAMP Induced Antitumor Effect and Its Application in Treating Cancer and Antibody Generation
Immunotherapy has shown promise in cancer treatment, yet most patients remain unresponsive to existing therapies. The cGAS-cGAMP-STING pathway, a notable target, primarily activates the innate immune system, inducing strong antitumor responses. Direct cGAMP delivery into tumors has demonstrated significant antitumor effects in vivo. Despite this, knowledge gaps persist regarding immune cell types in the tumor microenvironment and their impact on tumor immune surveillance via this pathway. Additionally, strategies for effectively combining the cGAS-STING pathway with other treatments to enhance therapeutic efficacy are still being explored. Chapter One reviews the cGAS-STING pathway's role in tumor immune surveillance and current strategies for targeting this pathway for antitumor efficacy. In Chapter Two, I reveal that cGAMP injection induces a macrophage population across various tumor types. These macrophages exhibit immune cell-attracting and antigen-presentation features, uncovering new mechanisms of cGAMP's antitumor effect. Chapters Three and Four discuss enhancing systemic antitumor effects by targeting the cGAS-STING pathway. Given cancer metastasis's significant mortality contribution, achieving a systemic antitumor effect is crucial. Currently, cGAMP's effect is localized, failing to control untreated distal tumors. Chapter Three demonstrates that combining Radiotherapy (RT) with cGAMP, followed by anti-PD-L1 immune checkpoint blockade, yields a systemic antitumor effect. This regimen induces dendritic cell maturation and modulates the CD8 T cell population, with findings suggesting CD4 T cell depletion could enhance efficacy at the cost of increased toxicity. Chapter Four describes developing an antibody-drug conjugate (ADC) that links a STING agonist to antibodies targeting EGFR, prevalent in many cancers. This STING ADC activates various immune cells and promotes macrophage polarization within tumors. Chapter Five utilizes cGAMP as an adjuvant to enhance the generation of SARS-CoV-2 antibodies, in which I identify a panel of high-affinity antibodies against various variants, including SW186. This antibody targets a conserved epitope on the spike protein. In summary, this thesis delves into the cGAS-cGAMP-STING pathway's therapeutic potential, from enhancing immune surveillance to developing strategies for systemic antitumor responses and viral defense.
Antibodies, Monoclonal, cGAS-STING Signaling Pathway, Immunotherapy, Macrophages, Neoplasms, Nucleotides, Cyclic, STING Protein
University of Texas Southwestern Medical Center
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