CD8+ T Cell-Mediated Immunotherapy of Autochthonous SV40 T Antigen-Induced Tumors

描述（由申请人提供）：近年来，由于CD8+ T细胞具有破坏肿瘤细胞的公认效力，因此开发了多种方法来招募CD8+ T细胞来控制癌症。迄今为止最有希望的方法之一是使用过继T细胞转移，在转移性黑色素瘤患者中取得了特别的成功。最近在确定促进有效的过继性T细胞免疫治疗癌症的机制方面取得了进展。然而，决定成功与失败的变量，特别是对于黑色素瘤以外的癌症，仍然没有明确的定义。本提案的总体目标是确定使用过继性T细胞免疫疗法促进CD8+ T细胞介导的消除已建立的原位肿瘤的机制。推动本研究的假设是，基于T细胞的过继免疫治疗癌症的有效性将随着肿瘤的不同组织学起源和靶向CD8+ T细胞表位的不同而变化，因为对肿瘤微环境的影响不同。将实现下列具体目标。具体目标明确放射增强过继免疫治疗后促进原位脑肿瘤消退的机制。具体目标2。评估来自特殊组织来源的肿瘤对过继性T细胞免疫治疗的敏感性。具体目标3。确定针对弱肿瘤相关决定因素的过继性T细胞免疫治疗的关键机制。在这项研究中，来自组织特异性启动子表达SV40大T抗原癌蛋白的小鼠将被用于研究调节对不同组织中出现的肿瘤进行有效过继T细胞免疫治疗的机制。这将包括脑癌、胰腺癌和前列腺癌的模型。SV40 T抗原系统提供了一个强大的模型来解决这些问题，因为有多种成熟的转基因小鼠肿瘤模型和大量试剂可用于监测T抗原特异性CD8+ T细胞对来自同一蛋白抗原的多种决定因素的反应。将定义与成功的T细胞介导的肿瘤消退相关的局部和全身辐射效应，以便更有针对性地设计针对已建立肿瘤的免疫疗法。此外，通过定义与成功免疫治疗相关的T细胞表型和肿瘤微环境的变化，将评估辐射增强过继T细胞转移控制独特组织学起源肿瘤的有效性。最后，我们将确定克服通过过继免疫治疗靶向弱肿瘤相关决定因素的局限性的方法，以扩大可用靶点的范围。通过在肿瘤系统中测试这些方法，其中抗原和效应T细胞群保持不变，这些研究的结果将揭示促进和/或抑制成功的过继T细胞免疫治疗的肿瘤特异性机制。这一新知识应该为增加针对不同癌症的转译过继性T细胞免疫治疗方法的成功提供见解。

DESCRIPTION (provided by applicant): A variety of approaches have been developed in recent years to recruit CD8+ T cells for the control of cancer due to their recognized potency to destroy tumor cells. One of the most promising approaches to date is the use of adoptive T cell transfer, with particular success in metastatic melanoma patients. Recent progress has been made toward defining the mechanisms that promote effective adoptive T cell-based immunotherapy of cancer. However, the variables that determine success versus failure, particularly for cancers beyond melanoma, remain poorly defined. The broad objective of this proposal is to identify mechanisms that promote CD8+ T cell-mediated elimination of established autochthonous tumors using adoptive T cell-based immunotherapies. The hypothesis driving this study is that the effectiveness of T cell- based adoptive immunotherapy of cancer will vary with the distinct histological origin of the tumor and the CD8+ T cell epitope targeted due to differential effects on the tumor microenvironment. The following specific aims will be pursued. Specific Aim 1. Define the mechanisms that promote regression of established autochthonous brain tumors following radiation-enhanced adoptive immunotherapy. Specific Aim 2. Evaluate the sensitivity of tumors from unique tissue origins to adoptive T cell immunotherapy. Specific Aim 3. Identify mechanisms critical for adoptive T cell immunotherapy targeting a weak tumor-associated determinant. In this study, mice that express the SV40 large T antigen oncoprotein from tissue-specific promoters will be used to investigate mechanisms that regulate effective adoptive T cell immunotherapy toward tumors that arise in distinct tissues. This will include models of brain, pancreas and prostate cancer. The SV40 T antigen system provides a powerful model to address these issues due to the availability of multiple well-established transgenic mouse tumor models and the large array of reagents available to monitor T antigen-specific CD8+ T cell responses to multiple determinants derived from the same protein antigen. Localized versus systemic effects of radiation associated with successful T cell-mediated tumor regression will be defined in order to more specifically design immunotherapies for established tumors. In addition, the efficacy of radiation-enhanced adoptive T cell transfer to control tumors of unique histological origin will be assessed by defining changes in the T cell phenotype and tumor microenvironments that are associated with successful immunotherapy. Finally, we will identify approaches that overcome the limitations of targeting a weak tumor-associated determinant by adoptive immunotherapy in order to broaden the repertoire of available targets. By testing these approaches in a tumor system where the antigen and the effectors' T cell population are held constant, the results of these studies should reveal tumor-specific mechanisms that promote and/or inhibit successful adoptive T cell-based immunotherapy. This new knowledge should provide insight for increasing the success of translational adoptive T cell-based immunotherapy approaches against diverse cancers. PUBLIC HEALTH RELEVANCE: The results of this study will further our understanding of how adoptive T cell-based immunotherapies can be applied to established cancers. The ability to apply this approach to multiple cancer types will be investigated and will provide insight for enhancement of this promising approach for the treatment of cancer.