Stimuli-responsive Delivery of Ectonucleotidase Inhibitors to Reprogram Immunometabolism in Head and Neck Cancer

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Summary Therapy-induced cancer immunity is limited by immunosuppressive mechanisms posed by the tumor microenvironment (TME). Cancer therapy triggers ATP release from cancer cells during the course of immunogenic cell death and extracellular ATP plays a pivotal role in the initiation of antitumor immunity by acting as a danger signal. However, extracellular ATP is quickly degraded into immunosuppressive adenosine via the concerted enzymatic activities of CD39 and CD73, dampening anticancer immunity. Systemic blockage of these enzymes often causes toxicity in normal tissues, where they protect the host from excessive immune activation. We hypothesize that stimuli-responsive delivery of CD39/CD73 inhibitors reprograms immunometabolism selectively in the TME, leading to effective and specific anticancer immunity without generating immune- mediated toxicity. We have prepared phenylboronic acid (PBA)-containing nanoparticles (NPs) for stimuli- responsive drug delivery. CD39 inhibitor ARL67156 (ARL), a nucleotide analogue, was loaded to the NPs through the interaction with PBA. The nucleotide drug can be released from the NPs through reactive oxygen species (ROS)-mediated degradation of PBA. Thus, we further loaded a photosensitizer IR700 on the NPs. Irradiation of the NPs with NIR light produced ROS that triggered ARL release from the NPs. On the other hand, photodynamic therapy (PDT) of tumor cells with the NPs caused extracellular ATP release. The released ARL prevented conversion of ATP to adenosine, thereby extending the immunogenic actions by PDT-released ATP and preventing adenosine-mediated immunosuppression. This change of immunometabolism landscape in the TME led to excellent tumor response in a mouse model of head and neck cancers that is resistant to immune checkpoint blockade. In this proposal, we will explore the mechanisms for TME reprograming after tumor delivery of ARL (Aim 1), and will enhance anticancer activity of CD39 inhibition by combination with other cancer immunotherapy for treating immunosuppressive tumors of head and neck cancers (Aim 2). Successful implementation of this project will ultimately lead to highly cancer specific and versatile delivery systems for cancer immunotherapy. By addressing lack of cancer specificity, a main obstacle for the development of next- generation immunotherapeutic regimens, we will contribute to a novel approach for precision delivery of immunotherapy.