Activation of the DNA-PK-dependent antiviral response as a novel cancer immunotherapy

Project Summary/Abstract Checkpoint blockade has revolutionized the field of cancer immunotherapy treatment, but many tumors remain unresponsive due to lack of effector T cell infiltration and activation in the tumor microenvironment. Innate immune priming of these “cold” tumors has emerged as a therapeutic strategy for increasing the efficacy of checkpoint blockade through stimulated type I interferon (IFN) production and downstream adaptive response. Recent efforts and ongoing clinical trials have focused on activation of the STING-dependent antiviral pathway to promote IFN production in the tumor microenvironment. However, many tumors downregulate STING signaling, and the therapeutic effects of STING agonists are thought to be mediated by their effects on tumor- infiltrating host myeloid cells. Our lab recently discovered that the DNA damage sensor DNA-PK triggers a STING-independent DNA sensing pathway (SIDSP) in human cells that potently activates IFN production in response to foreign DNA. We have developed synthetic superagonists of DNA-PK-dependent antiviral immunity that trigger potent antiviral responses in human melanoma cells that are unresponsive to STING agonists. We hypothesize that activation of the SIDSP within tumor cells will provide a unique signal to enhance inflammation within tumors and will stimulate potent immune responses. The goal of this proposal is to assess DNA-PK-SIDSP activation as a therapeutic strategy in human cancer. We will determine how DNA-PK directs distinct outcomes to DNA damage versus foreign DNA, and we will evaluate the therapeutic potential of triggering the DNA-PK-SIDSP in human tumors, in vitro and in vivo using cutting edge humanized mouse models. Our studies will uncover fundamental new aspects of the biology of the SIDSP, together with the first pre-clinical evaluation of DNA-PK activation as a novel cancer immunotherapy.