P4 - Regulatory T-Cells in the Tumor Microenvironment of B-Cell Non-Hodgkin

B细胞非霍奇金淋巴瘤（NHL）是常见的淋巴系统恶性肿瘤，其中T细胞浸润 淋巴细胞与患者的预后相关。尽管有广泛的抗肿瘤免疫研究， B细胞NHL中浸润性T细胞的病理生理学意义仍然知之甚少。最近的研究 已经表明，CD 4 + CD 25+调节性T（Treg）细胞参与抗肿瘤免疫的调节 通过诱导对肿瘤特异性抗原的外周耐受。然而，关于这种影响的数据很少。 Treg细胞对B细胞NHL中的肿瘤特异性T细胞免疫以及随后对恶性B细胞生长的影响。 在由SPORE开发奖支持的初步研究中，我们已经确定了CD 4 + CD 25+的一个子集， 此外，我们发现这些Treg细胞具有与B细胞NHL中存在的Treg细胞表型相同的表型。 抑制B细胞NHL中肿瘤浸润性T细胞的能力以及它们响应于诸如 如恶性B细胞产生的CCL 22。 我们的中心假设是肿瘤Treg细胞通过以下方式促进恶性淋巴瘤B细胞的生长： 抑制肿瘤浸润性T细胞，恶性B细胞通过选择性募集Treg发挥积极作用 B细胞NHL的区域。因此，我们建议首先确定这些Treg 细胞被募集到非霍奇金淋巴瘤的恶性B细胞微环境中， 当它们存在于肿瘤微环境中时是否获得抑制活性（Aim 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， 协调对他们存在的容忍（目标2）。第三，我们将确定肿瘤内Treg的耗竭是否 细胞，以及抑制恶性B细胞以减少Treg细胞募集，将导致临床益处， B细胞NHL患者（目的3）。 我们预计，拟议的研究将提供一个更好的了解Treg细胞介导的影响， B细胞恶性肿瘤我们还预计，地尼白介素diftitox的临床应用，白细胞介素-2和 白喉毒素融合蛋白与抗CD 20单克隆抗体利妥昔单抗联合， Treg细胞在B细胞淋巴瘤患者中的作用，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NHL

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.