Modulation of regulatory cell function in cancer immunotherapy

癌症免疫治疗中调节细胞功能的调节

• 批准号: 8187283
• 负责人: Piotr J. Kraj
• 金额: $ 30.95万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8187283
• 关键词: Affect; Antigen-Presenting Cells; Antigens; Autoantigens; CD4 Positive T Lymphocytes; Cancer Patient; Cell Count; Cell physiology; Cells; Cessation of life; Clonal Expansion; Connexin 43; Development; Effector Cell; Failure; Generations; Goals; Growth; Human; Immune; Immune response; Immune system; Immunity; Immunologic Monitoring; Immunotherapy; Inflammatory; Lesion; Lymphocyte Subset; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Memory; Mus; Normal tissue morphology; Peripheral; Phenotype; Population; Prostatic Neoplasms; Radiation; Radiation therapy; Regulatory T-Lymphocyte; Relative (related person); Research; Staging; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; T-Lymphocyte Subsets; Tissues; Tumor Antigens; Tumor Burden; Tumor-Derived; antigen processing; cancer immunotherapy; cancer therapy; conventional therapy; cytokine; hormone therapy; improved; neoplastic cell; pre-clinical; prevent; prognostic; response; transcription factor; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Understanding the interaction between tumor and immune system might help improve cancer immunotherapy. However, little is known how tumor associated antigens (TAA) regulate populations of effector and TR cells found in spontaneous responses in cancer. Since most TAAs are self-antigens it is not known how efficient they are to stimulate effector T cells and induce their clonal expansion. It is also not understood how TAAs induce and sustain regulatory CD4+ T cells (TR) expressing a transcription factor Foxp3+ which have been identified as the major obstacle to effective antitumor immunotherapy. We and others have determined that the population of TR cells in humans and mice is heterogeneous and TR subsets may have different, non-overlapping functions. The majority of TR cells present in healthy mice maintained a stable suppressor phenotype, expressed high level of Foxp3 and an exclusive set of TCRs not used by naive CD4+ T cells. A small TR subset, utilized TCRs shared with effector T cells and expressed a lower level of Foxp3 but could downregulate Foxp3 and produce inflammatory cytokines. This subset was found to dominate TR population in mice undergoing immune response to conventional antigens. It is not known how both TR subsets are regulated by self antigens in normal tissues, preclinical tumor lesions and in the course of tumor growth and which subset dominates the population of TR cells. In addition, it is not known if TR cells compromise cancer immune response starting at the initial stages of tumor growth or following a period of productive immune response. To reveal and understand cellular mechanisms of generating TR cells in cancer we will study how tolerance is established in peripheral tissues in mice bearing preclinically and clinically defined prostate tumors. We will further investigate how blocking expression of Foxp3 in effector and preexisting TR cells alleviates suppressor function of these cells, slows down growth or eradicates tumor cells and affects concurrent immunotherapy. This will be accomplished by modulating the expression of connexin 43, a molecule identified to control suppressor function of TR cells and expression of Foxp3. Finally, we will investigate how conventional hormonal and radiation therapy, commonly used to treat prostate cancer affect the generation and function of effector and TR cells specific for tumor antigens in mice with normal population of TR cells and mice where population of TR cells is greatly reduced. PUBLIC HEALTH RELEVANCE: Regulatory CD4+ T cells (TR) expressing a transcription factor Foxp3+ have been identified as the major obstacle to effective antitumor immunotherapy. To reveal and understand cellular mechanisms of generating TR cells in prostate cancer we will study how tolerance is established in peripheral tissue in mice bearing preclinically and clinically defined tumors. We will further investigate how blocking expression of Foxp3 in effector and preexisting TR cells alleviates suppressor function of these cells. This will be accomplished by modulating the expression of connexin 43, a molecule identified to control suppressor function of TR cells and expression of Foxp3. Finally, we will investigate how radiation and hormonal therapy, commonly used to treat prostate cancer affect the generation and function of effector and TR cells specific for tumor antigens in mice with normal population of TR cells and mice where TR cells are greatly reduced.

描述（由申请人提供）：了解肿瘤和免疫系统之间的相互作用可能有助于改善癌症免疫治疗。然而，人们对肿瘤相关抗原 (TAA) 如何调节癌症自发反应中的效应细胞和 TR 细胞群体知之甚少。由于大多数 TAA 是自身抗原，因此尚不清楚它们刺激效应 T 细胞并诱导其克隆扩增的效率如何。目前还不清楚 TAA 如何诱导和维持表达转录因子 Foxp3+ 的调节性 CD4+ T 细胞 (TR)，Foxp3+ 已被确定为有效抗肿瘤免疫治疗的主要障碍。 我们和其他人已经确定人类和小鼠的 TR 细胞群是异质的，TR 子集可能具有不同的、不重叠的功能。健康小鼠中存在的大多数 TR 细胞保持稳定的抑制表型，表达高水平的 Foxp3 和一组未被初始 CD4+ T 细胞使用的独特 TCR。一小部分 TR 子集利用与效应 T 细胞共享的 TCR，表达较低水平的 Foxp3，但可以下调 Foxp3 并产生炎症细胞因子。研究发现，在对传统抗原进行免疫反应的小鼠中，该子集在 TR 群体中占主导地位。目前尚不清楚正常组织、临床前肿瘤病变和肿瘤生长过程中这两个TR亚群如何受到自身抗原的调节，以及哪个亚群在TR细胞群中占主导地位。 此外，尚不清楚 TR 细胞是否会在肿瘤生长的初始阶段或一段有效的免疫反应期后损害癌症免疫反应。为了揭示和理解癌症中产生 TR 细胞的细胞机制，我们将研究患有临床前和临床定义的前列腺肿瘤的小鼠的外周组织如何建立耐受性。我们将进一步研究阻断效应细胞和预先存在的TR细胞中Foxp3的表达如何减轻这些细胞的抑制功能、减缓生长或根除肿瘤细胞以及影响同步免疫治疗。这将通过调节连接蛋白 43 的表达来实现，连接蛋白 43 是一种被鉴定为控制 TR 细胞抑制功能和 Foxp3 表达的分子。最后，我们将研究常用于治疗前列腺癌的常规激素和放射疗法如何影响 TR 细胞群正常小鼠和 TR 细胞群大幅减少的小鼠中肿瘤抗原特异性效应细胞和 TR 细胞的生成和功能。 公共健康相关性：表达转录因子 Foxp3+ 的调节性 CD4+ T 细胞 (TR) 已被确定为有效抗肿瘤免疫治疗的主要障碍。为了揭示和理解前列腺癌中产生 TR 细胞的细胞机制，我们将研究携带临床前和临床定义肿瘤的小鼠的外周组织如何建立耐受性。我们将进一步研究阻断效应细胞和预先存在的 TR 细胞中 Foxp3 的表达如何减轻这些细胞的抑制功能。这将通过调节连接蛋白 43 的表达来实现，连接蛋白 43 是一种被鉴定为控制 TR 细胞抑制功能和 Foxp3 表达的分子。最后，我们将研究常用于治疗前列腺癌的放射和激素疗法如何影响 TR 细胞群正常的小鼠和 TR 细胞大大减少的小鼠中肿瘤抗原特异性的效应细胞和 TR 细胞的生成和功能。