Cancer Cells and Stroma: Eradication of Established Cancer by CD8+ T

长期目标是通过过继转移肿瘤特异性基因来根除大型实体肿瘤。 CD8+T细胞。成功取决于CD8+T细胞：(I)通过以下方式消除大多数癌细胞 直接抗原特异性(穿孔素依赖)杀伤和(Ii)破坏非恶性肿瘤间质，在 与放射、化疗或激素治疗相结合，消除导致癌症的癌细胞变异 反复发作。这些目标是可以实现的，但已经使用转基因CD8+T细胞进行过继治疗， 表达肿瘤特异性抗原的癌细胞，缺乏调节性T细胞的荷瘤宿主，以及 移植瘤模型。挑战是如何证明这些条件将如何适用(并且可以 应用)用于消除动物体内的原发肿瘤，然后用于患者体内。因此，目标1是 确定过继转移T细胞根除或阻止大量已建立的患者的要求和限制 肿瘤。首先，将确定过继转移的T细胞是否能根除大鼠 已建立的移植肿瘤也可以摧毁生长在同一宿主和 表达相同抗原的。原发肿瘤对抗原致敏间质的能力 从癌细胞中释放出来的物质也进行了测试。在目标2中，将测试基质敏化和 间质破坏发生在不同的肿瘤类型中，以及外周T细胞能否有效地治疗 通过用自身反应性差的裂解T细胞中的TCR重新编程这些T细胞来破坏肿瘤间质。 一些癌症含有足够的抗原，在目标3中，通过以下方式从癌细胞释放这种抗原 治疗手法将尝试加载和敏化基质。如果癌细胞表达的太少 为了使间质致敏，将尝试用外源抗原加载间质。最后，通过 通过窗口打开对已建立的大肿瘤的光学成像，即事件的实时序列 将分析过继转移的T细胞遇到癌细胞和癌症间质时发生的情况。 这可能揭示过继转移的T细胞摧毁大的已建立的肿瘤和 癌症变异破坏的机制。 这些小鼠模型研究新的概念，并使用工程试剂摧毁大小的实体肿瘤 在患者身上可以检测到，即使在啮齿动物身上也能逃脱传统的免疫治疗。这个 计划是建立原则和开发新的方法，作为小说发展的指南 根除患者已有实体肿瘤的治疗方法。

The long-term objective is to eradicate large well-established solid tumors by adoptively transferred tumorspecific CD8+ T cells. Success depends on CD8+ T cells: (i) eliminating the majority of cancer cells by direct antigen-specific (perforin-dependent) killing and (ii) destroying non-malignant tumor stroma which in conjunction with radiation, chemo- or hormone therapy eliminates cancer cell variants responsible for recurrences. These objectives are obtainable, but have used transgenic CD8+ T cells for adoptive therapy, cancer cells expressing a tumor-specific antigen, tumor-bearing hosts lacking regulatory T cells, and a transplanted tumor model. The challenge is to demonstrate how these conditions will apply (and can be applied) to the elimination of autochthonous tumors in animals and then in patients. Thus, Aim 1 is to determine the requirements and limitations for adoptively transferred T cells to eradicate or arrest large wellestablished tumors. First it will be determined whether adoptively transferred T cells that eradicate large established transplanted tumors can also destroy autochthonous tumors growing in the same host and expressing the same antigen. The capability of the autochthonous tumors to sensitize stroma with antigen released from the cancer cells is also tested. In Aim 2, it will be tested whether stromal sensitization and stromal destruction occurs in different tumor types and whether peripheral T cells can be made effective to destroy tumor stroma by reprogramming these T cells with TCRs from self-reactive poorly lytic T cells. Some cancers harbor sufficient antigen, and in Aim 3, release of this antigen from the cancer cells by therapeutic manipulations will be attempted to load and sensitize the stroma. If cancer cells express too little antigen to sensitize stroma, loading of the stroma with exogenous antigen will be attempted. Finally, by optical imaging of well-established large tumors through a window opening, the real-time sequence of events will be analyzed that occur when adoptively transferred T cells encounter cancer cells and cancer stroma. This may reveal the primary targets of adoptively transferred T cells destroying large established tumors and the mechanisms of cancer variant destruction. These mouse models study novel concepts and use engineered reagents to destroy solid tumors of sizes that are detectable in patients and that escape conventional immunological therapies even in rodents. The plan is to establish principles and to develop novel approaches as a guide for the development of novel therapies to eradicate established solid tumors in patients.