The goal of this project is to define the mechanisms by which radioenhancing nanoscale metal-organic framework (nMOF) particles can be combined with immune modulators (IMs) to alter the immune microenvironment in order to facilitate checkpoint blockade immunotherapies of cancer. X-ray irradiation represents a significant treatment option for many cancer patients, and nMOFs possess a unique advantage by enabling the more effective radiotherapy-radiodynamic therapy (RT-RDT) at palliative X-ray doses. This new therapeutic strategy can synergize with current checkpoint blockade immunotherapy to treat localized, recurrent, and metastatic cancers. One nMOF formulation is currently undergoing clinical testing on patients with advanced tumors.

Specific Aim 1: Elucidate the cellular mechanisms of nMOF-mediated RT-RDT and IMs. Preliminary data indicated that RT-RDT is immunostimulatory, potentially initiating dendritic cell activation via the cGAS-STING pathway. We will test these working hypotheses in Aim 1.

Specific Aim 2: Profile tumor microenvironment and extracellular matrix after treatment with RT-RDT. Preliminary data demonstrated that RT-RDT can alter the TME by reducing the presence of protumor agents and increasing the activity of antitumor effects. We will test these working hypotheses: Aim 2.1, RT-RDT reduces cancer-associated fibroblasts in tumors. Aim 2.2, RT-RDT favors M1 macrophage polarization. Aim 2.3, RT-RDT increases activation of antigen presenting cells. Aim 2.4, RT-RDT causes T cell proliferation and activity in tumors.

Specific Aim #3: Investigate the anticancer efficacy and adaptive immune response of nMOF/IM-mediated RT-RDT and immunotherapy. nMOF-mediated RT-RDT has demonstrated strong anticancer efficacy in a variety of syngeneic tumors. Aim 3.1, irradiation of tumors injected with nMOF/IM eradicates tumors and initiates immune memory. Aim 3.2, eliminating any component of the immune system will reduce anticancer efficacy. Aim 3.3, nMOF/IM synergizes with checkpoint blockade for an abscopal effect.

Specific Aim 4: Determine novel immunotherapy combinations that are potentiated by RT-RDT in tumor models resistant to PD-1/PD-L1 blockade. Our preliminary data demonstrated that an autochthonous oral tumor model was resistant to RT-RDT and PD-1/PD-L1 blockade. We will test these working hypotheses: Aim 4.1, tumors resistant to PD-1/PD-L1 blockade upregulate compensatory immunosuppressive mechanisms. Aim 4.2, nMOF/IM coupled with alternative immunotherapies targeting compensatory immunosuppressive mechanisms cause RT-RDT mediated regression of primary oral tumors. Aim 4.3, nMOF/IMs and alternative immunotherapies enhance immune cell infiltration in tumors.

This research trains personnel in nanotechnology, materials science, in vitro and in vivo antitumor studies, radiotherapy, and tumor immunology. In addition, the personnel will gain practical experience in clinical translation of basic science discoveries.

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