Modulation of regulatory cell function in cancer immunotherapy

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发现的效应细胞和TR细胞群知之甚少。由于大多数TAA是自身抗原，因此不知道它们刺激效应T细胞并诱导其克隆扩增的效率如何。TAA如何诱导和维持表达转录因子Foxp3+的调节性CD4+ T细胞（TR）也不清楚，这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亚群可能具有不同的、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和未被初始CD4+ T细胞使用的一组排他性TCR。一个小的TR亚群，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并产生炎性细胞因子。发现该子集在经历对常规抗原的免疫应答的小鼠中占主导地位的TR群体。目前尚不清楚两种TR亚群如何在正常组织、临床前肿瘤病变和肿瘤生长过程中受自身抗原调节，以及哪一亚群主导TR细胞群。 此外，尚不清楚TR细胞是否在肿瘤生长的初始阶段或在产生免疫应答的一段时间后损害癌症免疫应答。为了揭示和理解在癌症中产生TR细胞的细胞机制，我们将研究如何在携带临床前和临床定义的前列腺肿瘤的小鼠的外周组织中建立耐受性。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的表达如何增强这些细胞的抑制功能，减缓生长或根除肿瘤细胞，并影响并行免疫治疗。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细胞的抑制功能和Foxp3表达的分子。最后，我们将研究如何传统的激素和放射治疗，通常用于治疗前列腺癌的影响的产生和功能的效应和TR细胞特异性的肿瘤抗原的小鼠与正常的TR细胞群和小鼠的TR细胞的人口大大减少。

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.