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: 8323881
• 负责人: Piotr J. Kraj
• 金额: $ 31.13万
• 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/8323881
• 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.

描述（由申请人提供）：了解肿瘤与免疫系统之间的相互作用可能有助于改善癌症免疫疗法。然而，鲜为人知的肿瘤如何调节癌症自发反应中发现的效应子和TR细胞的群体。由于大多数TAA是自我抗原，因此尚不清楚它们刺激效应T细胞和诱导其克隆膨胀的效率。也不了解TAA如何诱导和维持表达转录因子Foxp3+的调节性CD4+ T细胞（TR），该细胞已被确定为有效抗肿瘤免疫疗法的主要障碍。 我们和其他人已经确定人类和小鼠中TR细胞的种群是异质的，TR子集可能具有不同的非重叠函数。健康小鼠中存在的大多数TR细胞保持了稳定的抑制表型，表达了高水平的FOXP3和一组幼稚CD4+ T细胞未使用的TCR。一个小的TR子集，使用了与效应T细胞共享的TCR，并表达了较低的FOXP3水平，但可以下调Foxp3并产生炎症细胞因子。发现该子集在接受传统抗原的免疫反应的小鼠中占主导地位。尚不清楚两个TR子集在正常组织，临床前肿瘤病变和肿瘤生长过程中如何受到自抗原的调节，以及该子集主导TR细胞的群体。 此外，尚不清楚TR细胞在肿瘤生长的初始阶段还是在生产性免疫反应之后的初始阶段开始损害癌症免疫反应。为了揭示和理解癌症中TR细胞的细胞机制，我们将研究如何在具有临床和临床定义的前列腺肿瘤的小鼠外周组织中建立耐受性。我们将进一步研究FOXP3在效应子和先前存在的TR细胞中的表达如何减轻这些细胞的抑制功能，减慢生长或消除肿瘤细胞并影响并发的免疫疗法。这将通过调节连接蛋白43的表达来完成，该分子被鉴定出来控制TR细胞的抑制功能和FOXP3的表达。最后，我们将研究常规的激素和放射疗法如何用于治疗前列腺癌的通常如何影响效应子的产生和功能，而TR细胞群正常的TR细胞和小鼠的肿瘤抗原的发电和TR细胞的产生和功能大大降低。