Regulatory T-Cells in the Tumor Microenvironment of B-Cell Non-Hodgkin

B细胞性非霍奇金淋巴瘤(NHL)是一种常见的淋巴系统恶性肿瘤，其中T细胞的浸润性 淋巴细胞与患者的预后相关。尽管对抗肿瘤免疫进行了广泛的研究，但 B细胞非霍奇金淋巴瘤中T细胞浸润的病理生理学意义尚不清楚。最新研究 提示CD4+CD25+调节性T(Treg)细胞参与抗肿瘤免疫的调节 通过诱导外周对肿瘤特异性抗原的耐受。然而，关于这种影响的数据很少 研究Treg细胞对B细胞NHL肿瘤特异性T细胞免疫功能的影响，进而对恶性B细胞的生长产生影响。 在由孢子发育奖支持的初步研究中，我们已经确定了CD4+CD25+的一个子集 B细胞中存在的具有Treg细胞表型的T细胞。此外，我们发现这些Treg细胞具有 B细胞非霍奇金淋巴瘤中抑制肿瘤浸润性T细胞的能力及其对以下因素的反应 为恶性B细胞产生的CCL22。 我们的中心假设是肿瘤Treg细胞通过以下途径促进恶性淋巴瘤B细胞的生长 选择性募集Treg抑制肿瘤浸润性T细胞和恶性B细胞发挥积极作用 B细胞非霍奇金淋巴瘤的区域。因此，我们建议首先确定这些Treg 细胞被招募到非霍奇金淋巴瘤的恶性B细胞微环境中并发现 当它们存在于肿瘤微环境中时是否获得抑制活性(目标1)。其次，我们将 评估恶性B细胞是否与肿瘤微环境中的Treg细胞直接相互作用，从而 协调容忍他们的存在(目标2)。第三，我们将确定肿瘤内Treg的耗竭是否 抑制恶性B细胞以减少Treg细胞募集，将导致临床受益于 B细胞性非霍奇金淋巴瘤患者(AIM 3)。 我们预计，拟议的研究将提供对Treg细胞介导的效应的更好理解 在B细胞恶性肿瘤中。我们还预计德尼罗金、白介素2和白介素2的临床应用 白喉毒素融合蛋白与抗CD20的单抗利妥昔单抗结合将抑制 B细胞淋巴瘤患者的Treg细胞，也将耗尽恶性淋巴结中的淋巴瘤B细胞 从而防止Treg细胞进一步募集到B细胞淋巴瘤的区域。这种治疗组合 将导致一种新的治疗方法来调节Treg细胞，这将为患者带来临床益处 B细胞非霍奇金淋巴瘤。

B-cell non-Hodgkin lymphomas (NHL) are common lymphoid malignancies in which the infiltration of T lymphocytes correlates with the outcome of patients. Despite extensive studies on anti-tumor immunity, the pathophysiological significance of infiltrating T cells in B-cell NHL remains poorly understood. Recent studies have suggested that CD4+CD25+ regulatory T (Treg) cells are involved in the regulation of anti-tumor immunity by inducing peripheral tolerance to tumor specific antigens. However, there are little data regarding the effect of Treg cells on tumor-specific T cell immunity in B-cell NHL and subsequently on the malignant B-cell growth. In preliminary studies supported by a SPORE development award, we have identified a subset of CD4+CD25+ T cells with a Treg cell phenotype that are present in B-cell NHL.In addition, we find that these Treg cells have the ability to suppress tumor-infiltrating T cells in B-cell NHL and that they migrate in response to factors such as CCL22 produced by the malignant B-cells. Our central hypothesis is that tumor Treg cells contribute to the growth of malignant lymphoma B cells by suppressing tumor-infiltrating T cells and that malignant B-cells play an active role by selectively recruiting Treg cells to the areas of B-cell NHL. We therefore propose to firstly determine the mechanism by which these Treg cells are recruited to the malignant B-cell microenvironment in non-Hodgkin lymphoma and to discover whether they gain suppressive activity when present in the tumor microenvironment (Aim 1). Secondly, we will assess whether malignant B-cells interact directly with Treg cells in the tumor microenvironment and thereby orchestrate tolerance to their presence (Aim 2). Thirdly, we will establish whether depletion of intratumoral Treg cells, and inhibition of malignant B-cells to decrease Treg cell recruitment, will result in clinical benefit for patients with B-cell NHL (Aim 3). We anticipate that the proposed research will provide a better understanding of the Treg cell-mediated effects in B-cell malignancies. We also anticipate that the clinical use of denileukin diftitox, an interleukin-2 and diphtheria toxin fusion protein, in combination with rituximab, an anti-CD20 monoclonal antibody, will inhibit Treg cells in B-cell lymphoma patients and will also deplete lymphoma B-cells in malignant lymph nodes thereby preventing further recruitment of Treg cells into areas of B-cell lymphoma. This treatment combination will lead to a novel therapeutic approach to modulating Treg cells that will result in clinical benefit for patients with B-cellNHL.