While cancer immunotherapy targeting the adaptive immune system has led to prolonged disease-free survival in otherwise terminal patients, there are few effective cancer therapies that target the innate immune system. However, there is mounting evidence that the cGAMP-STING innate immunity pathway is a promising anti- cancer target. While cGAMP is synthesized and functions inside the cytoplasm, recent evidence has shown that cGAMP is exported by cancer cells and imported by cGAMP-sensing responder cells in the host, thereby acting as a paracrine immunotransmitter. However, the mechanisms by which cancer cells export cGAMP into the extracellular space and responder cells import cGAMP to activate intracellular STING are unclear. We previously described the reduced folate carrier SLC19A1 as the first known importer of cGAMP and other cyclic dinucleotides; however, it has not yet been demonstrated to play a physiological role within the tumor microenvironment. Likewise, the identities of the cGAMP exporter and the cGAMP-sensing responder cell populations remain unknown. The goal of this proposal is to further our understanding of cGAMP import and export in cancer. First, I will determine the role of SLC19A1 as a cGAMP importer in vivo using murine models of breast cancer. Then, I will confirm that our candidate cGAMP exporter, the xenobiotic exporter ABCG2, exports cGAMP in vitro in cell culture and in vivo in tumor models. Finally, I will demonstrate that intratumoral extracellular cGAMP induces host immune activation, and I will identify the initial cGAMP-sensing responder cells within the tumor microenvironment. This research will provide insight into cGAMP's role as an immunotransmitter and will advance the current model of how cGAMP activates the immune system in response to cancer, leading to novel targets for therapeutic intervention.
Therapeutics targeting the immune system are rapidly becoming mainstays of cancer therapy and the innate immune cGAMP-STING pathway is a promising new anticancer target. There is mounting evidence that cancer cells export cGAMP and host cells import cGAMP, leading to immune activation and tumor killing; however, the mechanism of cGAMP transport between cells is unclear. In this proposal I aim to characterize cGAMP import and export within the tumor microenvironment, as well as to identify cGAMP-sensing responder cell populations, in order to better understand how cGAMP activates the immune system in response to cancer.