Regulatory T cells in B cell lymphoma

描述（由申请人提供）：病理学家早就认识到，相当大比例的肿瘤块由浸润恶性肿瘤的非转化细胞组成。没有什么地方比B细胞淋巴瘤更令人着迷了。从机制上讲，浸润细胞被认为介导肿瘤促进和存活，或者通过免疫监视抵抗肿瘤进展。最近在某些淋巴瘤亚型基因表达谱方面的进展揭示了宿主免疫特征与临床预后之间的强相关性，提供了令人信服的证据表明癌症外在因素可能对癌症生物学产生深远影响。虽然在一些肿瘤中发现的高总体T细胞频率预示着有利的结果，但调节性T细胞（Tcells）的相对丰度与短期缓解和生存期降低相关。尽管几种细胞类型能够抑制肿瘤特异性免疫，但CD 4 + CD 25 + foxp 3 + T细胞的亚群似乎是免疫效应功能的最有效抑制剂之一。Treg生物学有几个特征与淋巴瘤发病机制特别相关。淋巴瘤已显示富含细胞因子如IL 10、IL 13和TGF 2，其促进Treg诱导或其抑制功能的扩增。由TcB产生的某些细胞因子可作为转化的B细胞的存活因子。最后，由于淋巴瘤细胞组成型表达MHC II类抗原，它们能够直接激活CD 4 + T细胞，阻断全身产生的（例如疫苗诱导的）T细胞应答的效应子功能的局部执行。该建议的中心焦点是使用动物模型充分表征TclB、T效应细胞和B细胞淋巴瘤之间的相互作用，目的是鉴定用于治疗操作的细胞和分子靶点。具体来说，我们将：1。使用B细胞恶性肿瘤的小鼠模型来确定Tcl 3对疾病进展的影响，以及支持Tcl 3诱导和/或扩增的肿瘤微环境的特征。2.确定淋巴瘤细胞直接MHC II抗原呈递在介导肿瘤部位抗淋巴瘤效应子应答的CD 4 + Treg依赖性抑制中的作用。3.检查靶向Treg耗竭的药物和抗体、Treg功能抑制剂以及寻求在达到耗竭后阻断Treg再诱导/募集的化合物的影响。 公共卫生相关性：淋巴瘤是免疫系统细胞的癌症。正常的免疫细胞可以对淋巴瘤产生警觉并试图消灭它。然而，一类细胞（所谓的调节性T细胞）可以抑制这一点。了解这些细胞如何工作将使策略绕过这种抑制。 淋巴瘤是免疫系统细胞的癌症。正常的免疫细胞可以对淋巴瘤发出警报并试图消除它。然而，一类细胞（所谓的调节性T细胞）可以抑制这种情况。了解这些细胞如何工作将使策略绕过这种抑制。

DESCRIPTION (provided by applicant): Pathologists have long recognized that a significant percentage of the mass of a tumor consists of non- transformed cells infiltrating the malignancy. Nowhere has the fascination with these responding host elements been greater than with B cell lymphomas. Mechanistically, the infiltrating cells have been implicated as mediating tumor promotion and survival, or alternatively resisting tumor progression through immune surveillance. Recent progress in profiling gene expression in certain lymphoma subtypes has revealed strong correlations between host immune signatures and clinical prognosis, providing compelling evidence that cancer-extrinsic factors can have a profound impact on cancer biology. While high overall T cell frequencies found within some tumors portend a favorable outcome, the relative abundance of regulatory T cells (Tregs) correlates with short remissions and decreased survival. Although several cell types are capable of suppressing tumor-specific immunity, a subset of CD4+CD25+foxp3+ T cells appears to be among the most potent inhibitors of immune effector function. There are several features of Treg biology that are especially relevant to lymphoma pathogenesis. Lymphomas have been shown to be rich in cytokines such as IL10, IL13, and TGF2, which promote Treg induction or amplification of their suppressive function. Some of the cytokines elaborated by Tregs may serve as survival factors for transformed B cells. Finally, as lymphoma cells constitutively express MHC class II antigens, they are capable of activating CD4+ Tregs directly, blocking the local execution of effector function of a systemically generated (e.g. vaccine induced) T cell response. The central focus of this proposal is to fully characterize the interactions between Tregs, T effector cells, and B cell lymphoma using animal models, with the objective of identifying cellular and molecular targets for therapeutic manipulation. Specifically, we will: 1. Use a mouse model of B cell malignancy to define the influence of Tregs on disease progression, and the features of the tumor microenvironment that support the induction and/or amplification of Tregs. 2. Define the role of direct MHC II antigen presentation by lymphoma cells in mediating CD4+ Treg dependent inhibition of anti-lymphoma effector responses at the site of tumor. 3. Examine the impact of drugs and antibodies targeting Treg depletion, inhibitors of Treg function, and compounds seeking to block Treg reinduction/recruitment once depletion has been achieved. PUBLIC HEALTH RELEVANCE: Lymphomas are cancers of the cells of the immune system. Normal immune cells can become alerted to lymphoma and attempt to eliminate it. However one class of cells (so-called regulatory T cells) can inhibit this. Understanding how these cells work will enable strategies to bypass this suppression. Lymphomas are cancers of the cells of the immune system. Normal immune cells can become alerted to lymphoma and attempt to eliminate it. However one class of cells (so-called regulatory T cells) can inhibit this. Understanding how these cells work will enable strategies to bypass this suppression.