Immune Escape in Human Cancer: Mechanisms and Therapeutic Implications

描述（由申请人提供）：本次PPG的目标是探索现代肿瘤免疫学的主要未解决问题之一，即免疫细胞在肿瘤微环境中的命运。目前的假设是，在癌症患者中，免疫细胞无法有效地介导抗肿瘤活性，因为人类肿瘤细胞可以逃避免疫应答，或主动干扰免疫效应细胞的分化、功能和/或存活。免疫治疗（包括抗肿瘤疫苗）控制肿瘤生长的失败可能是由于肿瘤介导的免疫系统功能障碍和/或肿瘤细胞进化出的成功策略来避免免疫检测。这些假设是基于我们的初步数据记录功能障碍，Th2偏差和循环CD8+ T细胞自发凋亡；树突状细胞（DC）分化缺陷；以及肿瘤细胞抗原加工机制（APM）和抗原递呈的畸变。在四个核心支持的四个项目中，该PPG将试图剖析抗肿瘤免疫反应中这些异常的机制。提高对这些机制的理解对于开发新的治疗策略至关重要，这些策略旨在保护肿瘤特异性效应T细胞免于凋亡，恢复平衡的Th1/Th2反应，DC的充分极化和功能，以及改善肿瘤细胞表面hla类l-肿瘤肽复合物的呈现。细胞因子及其对淋巴细胞存活和肿瘤逃逸的影响将在体外和体内进行评估，作为拟议临床试验的一部分。在项目1中，将研究HNC或黑色素瘤患者循环肿瘤特异性CD8+ T细胞的自发凋亡。项目2将探索肾细胞癌患者肿瘤抗原特异性T辅助细胞免疫偏差的分子和功能后果。在项目3中，将开发用于检测和定量hla - i类肿瘤肽复合物的新型scFv探针，并与针对APM成分的抗体一起用于研究HNC患者肿瘤逃逸的机制。评估经IFN-y治疗后APM缺损及其修复的临床意义。为了实现这些目标，PPG汇集了在癌症免疫学/免疫治疗方面经验丰富的基础和临床研究人员。总体目标是防止肿瘤细胞逃逸，从而提高抗肿瘤免疫疗法的有效性。

DESCRIPTION (provided by applicant): The goal of this PPG is to explore one of the major unsolved problems of modern tumor immunology, namely, the fate of immune cells in the tumor microenvironment. The working hypothesis is that in the patients with cancer, the immune cells are unable to effectively mediate anti-tumor activities, because human tumor cells can escape from the immune response and/or actively interfere with the differentiation, function and/or survival of immune effector cells. The failure of immunotherapy, including anti-tumor vaccines, to control tumor growth probably results from tumor-mediated dysfunction of the immune system and/or from successful strategies evolved by tumor cells to avoid immune detection. These hypotheses are solidly based on our preliminary data documenting dysfunction, Th2 deviation and spontaneous apoptosis of circulating CD8+ T cells; differentiation defects in dendritic cells (DC); and aberrations in the antigen processing machinery (APM) and antigen presentation by tumor cells. In four projects supported by four cores, this PPG will attempt to dissect mechanisms responsible for these abnormalities in anti-tumor immune responses. An improved understanding of these mechanisms is essential for the development of novel therapeutic strategies designed to protect tumor-specific effector T cells from apoptosis and restore balanced Th1/Th2 responses, adequate polarization and functions of DC as well as improved presentation of HLA-class l-tumor peptide complexes on the tumor cell surface. Cytokines and their impact on lymphocyte survival and tumor escape will be evaluated in vitro and in vivo, as part of the proposed clinical trials. In Project 1, spontaneous apoptosis of circulating tumor-specific CD8+ T cells will be investigated in patients with HNC or melanoma. Project 2 will explore molecular and functional consequences of immune deviation in tumor-antigen specific T helper cells in patients with renal cell cancer. In Project 3, new scFv probes for detection and quantitation of HLA-class I-tumor-peptide complexes will be developed and, together with antibodies to APM components, used for studies of mechanisms that contribute to tumor escape in patients with HNC. Clinical significance of APM defects and their repair upon therapy with IFN-y will be assessed. To accomplish these objectives, the PPG brings together basic and clinical investigators experienced in cancer immunology/immunotherapy. The overall goal is to prevent tumor cell escape and thereby improve effectiveness of anti-tumor immunotherapies.