Harnessing antiviral memory T cells for tumor immunotherapy

Abstract

Overcoming the immunosuppressive tumor microenvironment remains a major impediment to successful cancer immunotherapy. Virus-specific memory T cells are positioned throughout the entire body to sense reinfection or recrudescence. Mouse models have demonstrated upon reencountering cognate antigen, these tissue resident memory T cells (T_RM) induce a local immunostimulatory environment that activates and recruits innate and adaptive arms of the immune system, and we extend these functions to include recruitment of circulating antibody. Like healthy tissue, we observe that mouse and human tumors are commonly surveyed by virus-specific memory CD8+ T cells. This was seen in a range of tumor types including traditionally ‘immune-privilege’ tissues such as glioblastoma. Given the described immunostimualtory functions of antiviral T_RM in healthy tissue, we tested if we could leverage antiviral CD8+ T cells in tumors as an immunotherapy. Local delivery of adjuvant-free peptide derived from previously encountered viruses successfully reactivated antiviral T cells within melanoma and glioblastoma tumors. This arrested growth of checkpoint blockade-resistant and poorly immunogenic tumors in mice. Antiviral T cell reactivation triggered antigen presentation and cytotoxic pathways within the tumor, activating T cells, dendritic cells and natural killer cells. Viral peptide treatment of ex vivo human tumors demonstrated upregulation of immune activation gene expression profiles similar to those observed in mice. Lastly, viral peptide therapy renders resistant mouse tumors susceptible to PD-L1 blockade. Thus, re-stimulating known antiviral immunity may provide a novel therapeutic approach for a broad range of tumors.