Regulatory T cells in B cell lymphoma

描述（由申请人提供）：病理学家很早就认识到，肿瘤肿块中有很大一部分是由浸润恶性肿瘤的非转化细胞组成的。没有什么比B细胞淋巴瘤更让人着迷的了。从机制上讲，浸润细胞参与了肿瘤的促进和存活，或者通过免疫监视抵抗肿瘤的进展。在某些淋巴瘤亚型中基因表达谱的最新进展揭示了宿主免疫特征与临床预后之间的强相关性，为癌症外部因素可能对癌症生物学产生深远影响提供了令人信服的证据。虽然在某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（Tregs）的相对丰度与短期缓解和生存率降低相关。虽然有几种细胞类型能够抑制肿瘤特异性免疫，但CD4+CD25+foxp3+ T细胞亚群似乎是免疫效应功能最有效的抑制剂之一。Treg的几个生物学特征与淋巴瘤的发病机制特别相关。淋巴瘤富含细胞因子，如IL10、IL13和TGF2，这些细胞因子促进Treg诱导或扩增其抑制功能。Tregs产生的一些细胞因子可能作为转化B细胞的存活因子。最后，由于淋巴瘤细胞组成性地表达MHC II类抗原，它们能够直接激活CD4+ Tregs，阻断系统产生的（例如疫苗诱导的）T细胞反应的局部效应功能的执行。本提案的中心焦点是利用动物模型充分表征Tregs， T效应细胞和B细胞淋巴瘤之间的相互作用，目的是确定治疗操作的细胞和分子靶点。具体来说，我们将：1。使用B细胞恶性肿瘤小鼠模型来确定Tregs对疾病进展的影响，以及支持Tregs诱导和/或扩增的肿瘤微环境特征。明确淋巴瘤细胞直接递呈MHC II抗原在肿瘤部位介导CD4+ Treg依赖性抑制抗淋巴瘤效应反应中的作用。3. 检查靶向Treg耗尽的药物和抗体、Treg功能抑制剂以及一旦Treg耗尽后寻求阻断Treg再诱导/募集的化合物的影响。

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.