The Role of CD5 in Tumor Immunity

摘要 树突状细胞(DC)在抗肿瘤免疫反应的调节中发挥重要作用。在小鼠和 人类，DC由不同的子集组成，这些子集具有内在的差异，导致在 一代的豁免权。与老鼠相比，人们对人类组织的功能分类知之甚少。 常驻DC，以及疾病中亚群分布是如何改变的。我的实验室发表了开创性的研究 人树突状细胞亚群的鉴定及其控制细胞功能的研究 和体液免疫。这个应用程序主要关注我们最近发现的一种新的人类DC子集 由CD5表达描述，我们最初在人类皮肤、血液和淋巴结中发现了这一点。CD5+DC 在老鼠和人类身上都存在。它们有效地将T细胞极化为辅助性和细胞毒性反应，并且 与健康组织相比，受影响的黑色素瘤组织中它们的数量减少。使用人类DC的初步数据 并提供临床前小鼠模型以证明CD5是DC上维持 体内T细胞活化与肿瘤排斥反应。 虽然晚期黑色素瘤患者的生存期已经通过增强T细胞的干预措施而延长 激活后，反应仅限于少数患者。因此，我们假设利用CD5 DC上的共刺激系统将有助于产生广泛的T细胞反应和 完全清除黑色素瘤细胞所需的免疫记忆。要解决这个问题 假设，我们将1)利用我们实验室开发的新的小鼠模型来定义 DC或T细胞表面CD5在肿瘤免疫、抗肿瘤疫苗接种和形成对检查点的反应中的作用 阻断治疗；2)确定激活和抗肿瘤T反应的分子相互作用 CD5+DC；3)确定慢性粒细胞白血病患者CD5+DC的分布和功能是否恢复 对检查点阻断治疗有反应的黑色素瘤。 这些研究将促进我们对树突状细胞靶向功能的新机制的理解 并将为在治疗环境中利用CD5+DC生物学提供理论基础。

ABSTRACT Dendritic cells (DCs) play critical roles in the regulation of anti-tumor immune responses. In both mice and humans, DCs consist of distinct subsets with intrinsic differences that lead to functional specialization in the generation of immunity. Compared to mice, little is known about the functional classification of human tissue- resident DCs, and how subset distribution is altered in disease. My laboratory has published pioneering studies on the identification and functional characterization of human DC subsets with respect to their control of cellular and humoral immunity. This application focuses on our recent discovery of a new human DC subset that is delineated by CD5 expression and that we discovered initially in human skin, blood and lymph nodes. CD5+ DCs are present in both mice and humans. They efficiently polarize T cells into helper and cytotoxic responses, and their number is reduced in melanoma affected compared to healthy tissue. Preliminary data using human DCs and pre-clinical mouse models are provided to demonstrate that CD5 is a critical molecule on DCs that sustains T cell activation and tumor rejection in vivo. Although the survival of advanced melanoma patients has been extended by interventions that enhance T cell activation, the response is limited to a minority of patients. Thus, we hypothesize that harnessing the CD5 costimulatory system on DCs will contribute towards the generation of a broad T cell response and immunological memory that is required to completely eliminate melanoma cells. To address this hypothesis, we will 1) harness novel murine models developed in our laboratory to define the requirement of CD5 on either DCs or T cells in tumor immunity, anti-tumor vaccination and in shaping response to checkpoint blockade therapy; 2) determine the molecular interactions underlying the activation and anti-tumor T responses by CD5+ DCs; 3) determine whether the distribution and the function of the CD5+ DCs is restored in patients with melanoma that respond to checkpoint blockade therapy. These studies will advance our understanding of a novel mechanism by which dendritic cells function to target cancer cells and will provide a rationale for harnessing CD5+ DC biology in a therapeutic setting.