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

研究报告称，持续病毒感染的患者患癌症的风险增加，特别是逆转录病毒和疱疹病毒感染。然而，到目前为止，关于慢性/潜伏病毒感染对抗肿瘤免疫的影响的研究还很少。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，在大多数癌症模型中是抗肿瘤免疫所必需的。慢性Friend逆转录病毒(FV)和潜伏的小鼠巨细胞病毒(MCMV)或单纯疱疹病毒(HSV)感染可诱导细胞毒性T细胞和NK细胞反应，有助于控制小鼠体内的这些持续病毒。由于病毒的持久性，这些细胞毒性的CD4T和NK效应细胞被持续激活，但目前尚不清楚它们对肿瘤免疫监测是有利还是有害。利用FV模型，我们证明了移植的FBL-3肿瘤细胞在幼稚小鼠中可以被细胞毒性T细胞排斥，但在慢性FV感染的小鼠中会逐渐生长。因此，慢性感染干扰了细胞毒性T细胞反应，这是由抑制性调节性T细胞(Treg)的大量扩张所解释的。此外，单纯疱疹病毒感染可导致Tregs的深刻扩张。因此，我们将分析病毒诱导的CD4T和NK细胞在FV和HSV持续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功能的策略。与之形成鲜明对比的是，巨细胞病毒感染不会扩大Tregs，但其特征是细胞毒性T细胞和NK细胞的激活程度是病毒感染中已知的最强之一。这种强烈的细胞毒性反应可促进抗肿瘤免疫和肿瘤细胞排斥反应。我们将在小鼠模型中仔细比较不同持续病毒感染在细胞和分子水平上的这些有害和有益的影响。为了确定我们在小鼠模型中的发现的临床意义，我们将分析潜伏的人类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细胞反应的影响。我们将确定CMV/HSV特异性的CD4T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Tregs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细胞反应。我们将研究在免疫检查点阻断治疗和治疗相关免疫相关不良事件下，潜伏的CMV和HSV感染在临床反应中的作用。因此，我们计划剖析持续感染诱导的肿瘤免疫调节的免疫学机制。

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.