Chronic/latent viral infections modulate the function of cytotoxic T cells and natural killer cells with antitumor activity

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Studies reported an increased risk of cancers among patients with persistent viral infections, especially retroviruses and herpes virus infections. However, the influence of chronic/latent viral infections on antitumor immunity has so far been poorly investigated. We will study the role of cytotoxic T cells and natural killer (NK) cells because such cells are strongly activated by many viral infections and are essential for antitumor immunity in most cancer models. Chronic Friend retrovirus (FV) and latent murine cytomegalovirus (MCMV) or herpes simplex virus (HSV) infections induce cytotoxic T-cell and NK cell responses that contribute to the control of these persistent viruses in mice. Because of viral persistence, these cytotoxic CD4 T and NK effector cells are continuously activated, but it remains unclear whether they are beneficial or detrimental for tumor immune surveillance. Using the FV model, we demonstrated that transplanted FBL-3 tumor cells can be rejected by cytotoxic T cells in naïve mice but grow progressively in chronically FV-infected mice. Thus, the chronic infection interferes with the cytotoxic T-cell response, which is explained by the massive expansion of suppressive regulatory T cells (Treg). Also, HSV infection induces a profound expansion of Tregs. Thus, we will analyze the antitumor activity of virus-induced CD4 T and NK cells in persistently FV- and HSV-infected mice and will define strategies enhancing their effector functions after tumor challenge. In sharp contrast, CMV infection does not expand Tregs but is characterized by one of the strongest activations of cytotoxic T and NK cells known in virus infections. This strong cytotoxic response can contribute to antitumor immunity and tumor cell rejection. We will carefully compare these detrimental and beneficial effects of different persistent viral infections at the cellular and molecular level in mouse models. To determine the clinical significance of our findings from mouse models, we will analyze the effect of latent human CMV and HSV-1 infections on cytotoxic antitumor T- and NK-cell responses among melanoma patients. We will determine whether CMV/HSV-specific CD4 T cells and virus-induced memory-like NK cells contribute to melanoma cell killing or whether the induction of Tregs restricts melanoma-reactive T- and NK-cell responses of melanoma patients. We will study the role of latent CMV and HSV infection in clinical responses under immune checkpoint blocking therapy and therapy-associated immune-related adverse events. Thus, we plan to dissect immunological mechanisms involved in the modulation of tumor immunity that are induced by persistent infections.