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

研究报告称，持续性病毒感染，特别是逆转录病毒和疱疹病毒感染的患者患癌症的风险增加。然而，慢性/潜伏病毒感染对抗肿瘤免疫的影响迄今为止研究甚少。我们将研究细胞毒性T细胞和自然杀伤（NK）细胞的作用，因为这些细胞被许多病毒感染强烈激活，并且在大多数癌症模型中对抗肿瘤免疫至关重要。慢性Friend逆转录病毒（FV）和潜伏性鼠巨细胞病毒（MCMV）或单纯疱疹病毒（HSV）感染诱导细胞毒性T细胞和NK细胞应答，有助于控制小鼠中的这些持久性病毒。由于病毒的持续存在，这些细胞毒性CD 4 T和NK效应细胞被持续激活，但仍不清楚它们对肿瘤免疫监视是有益还是有害。使用FV模型，我们证明了移植的FBL-3肿瘤细胞可以被幼稚小鼠中的细胞毒性T细胞排斥，但在慢性FV感染的小鼠中进行性生长。因此，慢性感染干扰细胞毒性T细胞应答，这可以通过抑制性调节性T细胞（Treg）的大量扩增来解释。此外，HSV感染诱导THBG的显著扩张。因此，我们将分析病毒诱导的CD 4 T和NK细胞在持续FV和HSV感染的小鼠中的抗肿瘤活性，并将确定在肿瘤攻击后增强其效应子功能的策略。与此形成鲜明对比的是，CMV感染不会扩增T细胞，但其特征在于病毒感染中已知的细胞毒性T细胞和NK细胞的最强激活之一。这种强烈的细胞毒性反应可有助于抗肿瘤免疫和肿瘤细胞排斥。我们将在小鼠模型中仔细比较不同持续性病毒感染在细胞和分子水平上的有害和有益作用。为了确定我们在小鼠模型中发现的临床意义，我们将分析潜伏的人CMV和HSV-1感染对黑色素瘤患者细胞毒性抗肿瘤T细胞和NK细胞应答的影响。我们将确定CMV/HSV特异性CD 4 T细胞和病毒诱导的记忆样NK细胞是否有助于黑色素瘤细胞的杀伤，或者Tcl 3的诱导是否限制了黑色素瘤患者的黑色素瘤反应性T细胞和NK细胞应答。我们将研究潜伏CMV和HSV感染在免疫检查点阻断治疗和治疗相关免疫相关不良事件的临床反应中的作用。因此，我们计划剖析参与持续感染诱导的肿瘤免疫调节的免疫机制。

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.