Repurposing TRM for tumor immunotherapy Overcoming the immunosuppressive tumor microenvironment and localizing adoptive cell and checkpoint blockade therapies to solid tumors remain major impediments to successful cancer immunotherapy. This proposal addresses these issues. Preliminary data indicates that human tumors are populated with antiviral T cells that remain competent to trigger immunostimulatory sensing and alarm function upon local recognition of cognate peptide. In mice, peptide alarm therapy synergizes with PD-L1 to clear tumors and mice are durably protected against tumor growth at alternative anatomic sites in the absence of further treatment. This proposal will dissect the mechanisms by which peptide alarm therapy triggers tumor clearance and establishes systemic tumor-specific immunity. It will test synergy with other immunotherapies. Further investigations will be made on the ability to recapitulate peptide alarm therapy on human tumor explants in anticipation of informing a clinical trial. This proposal may have a sustained impact on the field by defining a new avenue of cancer immunotherapy that operates independently but synergizes with other therapies.
The goal of this proposal is to define the mechanism of a new strategy of immunotherapy: peptide alarm therapy. Further investigations will test the potential for synergizing peptide alarm therapy with other immunotherapies and for testing abscopal effects in mouse cancer models, followed by evaluation of peptide alarm therapy-induced sensing and alarm functions in human tumor explants. Successful execution should provide the necessary information to proceed with a clinical trial for the treatment of human cancer.