PROJECT SUMMARY/ABSTRACT
Recent studies have revealed an abundance of resident memory T cells (TRM) specific for viral infections in a
wide range of tumors, often outnumbering cancer-specific T cells. As these cells lack specificity to tumor
antigens, they are spared from the hallmark exhaustion/dysfunction of tumor-specific T cells. To this end, we
developed a novel immunotherapy which taps into immunostimulatory virus-specific TRM functions through
treatment with viral peptides to break the immunosuppressive tumor environment. Reactivating virus-specific
TRM with peptide was sufficient to restrict tumor growth in mice and when combined with checkpoint blockade,
promoted durable tumor clearance. Mice that cleared tumors were protected from tumor re-challenge, suggesting
anti-tumor immunity was established. Virus-specific TRM represent a major part of the tumor immune environment
and can be leveraged therapeutically, yet there is a clinically significant gap in knowledge regarding the
mechanisms of tumor clearance and how to optimally harness these cells. The objectives in this proposal are to
determine (i) mechanism of tumor cell killing and durable tumor immunity, (ii) the impact of viral specificity on
TRM function and therapeutic efficacy, and iii) define the optimal modality to reactivate virus-specific TRM. Using
both mouse and human systems, this study addresses an innovative perspective connecting antiviral memory
cells to tumor immunotherapy using cutting edge methods. We will complement mouse studies with
combinatorial tetramer staining to enable simultaneous profiling of T cells specific for an expanded panel of
viruses and vaccines in patient tumors. Completion of these aims will advance our understanding of tumor
immunosurveillance and TRM function in mice and humans, and identify new target T cell populations for tumor
immunotherapy. This contribution is expected to be significant because it will provide a strong scientific
framework to expand the efficacy and utility of virus-specific TRM therapy, and enable the development of novel
strategies leveraging these potent immune activating cells.