Naïve T cell archetypes and anti-tumor immunity

项目摘要/摘要 T细胞免疫疗法给癌症治疗带来了革命性的变化，强调了这些细胞控制癌症的能力。 肿瘤生长。尽管如此，到目前为止，T细胞免疫治疗只利用了效应性T细胞。天真的T 细胞是T细胞免疫的原始底物。我们和其他人最近发现，天真 T细胞以不同的转录异质性状态存在，包括表现为静止表型的簇状细胞 或表达I型干扰素反应基因或IL-4反应基因或TCR途径基因或记忆样基因 基因。幼稚T细胞的异质性不是固定的，而是对遗传或环境信号非常敏感。值得注意的是， 由突变或病原体经验引起的簇组成的变化可能会有显著的影响，在某些情况下 在一些病例中，幼稚T细胞对同种抗原的反应能力完全相反。我们把它放在这里 提出幼稚T细胞是微生物经验的储存库这一创新概念。这反过来又建立了 在同源抗原相遇期间，包括在抗肿瘤免疫反应期间，它们未来的激活潜力。 我们建议：(1)测试病原体暴露对幼稚CD4+和CD8+转录异质性的影响。 CD8+T细胞和(2)与原始T细胞固有的这些抗原不可知的转录变化相关 对抗肿瘤免疫反应的影响。我们的方法将包括测试一系列微生物体验 (即：细菌、病毒和蠕虫感染)，以全面描述不同类型感染的影响。 建立经验塑造的幼稚T细胞转录状态与其能力之间的关系 为了建立抗肿瘤免疫反应，我们将测试病原体条件下的幼稚T细胞 自体肿瘤模型。我们的建议有可能改变我们对 环境在幼稚T细胞水平上塑造免疫状态，并由此对免疫产生影响， 包括抗肿瘤免疫。

PROJECT SUMMARY/ABSTRACT T cell immunotherapy have revolutionized cancer treatment, underscoring the ability of these cells in controlling tumor growth. Notwithstanding, T cell immunotherapy, heretofore, has only exploited effector T cells. Naïve T cells are the primordial substrate of T cell-mediated immunity. We and others have recently discovered that naïve T cells exist in distinct transcriptionally heterogenous states including clusters displaying a quiescent phenotype or expressing type I interferon response genes or IL-4 response genes or TCR pathway genes or memory-like genes. Naïve T cell heterogeneity is not fixed, but rather sensitive to genetic or environmental signals. Notably, changes in cluster composition induced by mutations or pathogen experience can have significant and, in some cases, diametrically opposite effects in the ability of naïve T cells to respond to cognate antigen. Here we put forward the innovative concept that naïve T cells are a repository of microbial experience. This in turn, establishes their future activation potential during cognate antigen encounter, including during anti-tumor immune response. We propose to: (1) test the effect of pathogen exposure on the transcriptional heterogeneity of naïve CD4+ and CD8+ T cells and (2) correlate these antigen-agnostic transcriptional changes intrinsic to naïve T cells for their effect on anti-tumor immune responses. Our approach will include testing a spectrum of microbial experiences (i.e.: bacterial, viral, and helminth infection) to comprehensively profile the effect of different types of infections. To establish the relationship between experience-moulded transcriptional states of naïve T cells and their ability to mount an anti-tumor immune response, we will test pathogen-conditioned naïve T cells in implanted and authoctonous tumor models. Our proposal has the potential to transform our understanding on how the environment shapes the immune state at the level of naïve T cells and the consequent impact on immunity, including anti-tumor immunity.