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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 (TRM) 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 TRM 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.

Lymphocytic choriomeningitis virus (LCMV) is a natural mouse pathogen. LCMV Armstrong, an acutely resolved strain, and LCMV Clone13, a mutant that establishes chronic infection, have provided contrasting infection models that continue to inform the fundamental biology of T cell differentiation, regulation of exhaustion, and response to checkpoint blockade. Here, we describe LCMV Minnesota (LCMV-MN), which was transmitted to laboratory mice upon cohousing with pet shop mice and shares 80–95% amino acid homology with previously characterized LCMV strains. Infection of laboratory mice with purified LCMV-MN resulted in widely disseminated viral replication and viremia that was controlled within 15–30 days; which is of intermediate duration between LCMV Armstrong and Clone13. The magnitude of the LCMV-MN specific CD8+ T cell was maintained at much higher levels than that observed after LCMV Armstrong or Clone13 infections. LCMV-MN responding CD8+ T cells were further associated with significantly biased differentiation towards the recently described PD1+ CXCR5+ Tim-3lo stem-like CD8+ T cell population that was previously shown to be largely responsible for responsiveness to PD-1 inhibitory checkpoint blockade. In contrast to LCMV Clone13-induced responses, this subset persisted after resolution of LCMV-MN viremia, yet transcriptionally, phenotypically and functionally resembled PD1+ TCF1+ stem-like CD8+ T cells maintained by LCMV Clone13 infection. Together with existing models, LCMV-MN may contribute to a better understanding of the breadth of immune response in different chronic infections or tumor settings as well as the regulation of responsiveness to PD-1 blockade.

Central memory T (TCM) cells patrol lymph nodes and perform conventional memory responses upon re-stimulation: proliferation, migration, and differentiation into diverse T cell subsets while also self-renewing. Resident memory T (TRM) cells are parked within single organs, share properties with terminal effectors, and contribute to rapid host protection. We observed that reactivated TRM cells rejoined the circulating pool. Epigenetic analyses revealed that TRM cells align closely with conventional memory T cell populations, bearing little resemblance to recently activated effectors. Fully differentiated TRM cells isolated from small intestine epithelium exhibited the potential to differentiate into TCM, TEM, and TRM cells upon recall. Ex-TRM cells, former intestinal TRM that rejoined the circulating pool, heritably maintained a predilection for homing back to their tissue of origin upon subsequent reactivation and a heightened capacity to re-differentiate into TRM cells. Thus, TRM cells can rejoin the circulation but are advantaged to re-form local TRM when called upon.