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

长期目标是通过过继转移的肿瘤特异性靶向治疗来根除大的已建立的实体瘤。 CD8+ T细胞。成功取决于CD8+ T细胞：（i）通过免疫抑制消除大多数癌细胞。 直接抗原特异性（穿孔素依赖性）杀伤和（ii）破坏非恶性肿瘤间质， 结合放射、化疗或激素治疗，消除了癌细胞变异， 反复发作。这些目标是可以实现的，但是已经使用转基因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，和 移植瘤模型挑战在于证明这些条件将如何适用（以及可以如何适用）。 应用于）消除动物中的自体肿瘤，然后在患者中。因此，目标1是 确定过继转移的T细胞消除或阻止大的已建立的免疫缺陷的需要和限制。 肿瘤的首先，将确定是否过继转移的T细胞，消除大的 已建立的移植肿瘤也可以破坏在同一宿主中生长的自体肿瘤， 表达相同的抗原自体肿瘤抗原致敏基质的能力 从癌细胞中释放出来的物质也被检测。在目标2中，将测试基质致敏和 基质破坏发生在不同的肿瘤类型中，外周T细胞是否可以有效地 通过用来自自身反应性较差的溶解性T细胞的TCR重编程这些T细胞来破坏肿瘤基质。 一些癌症具有足够的抗原，并且在目标3中，通过免疫抑制剂从癌细胞释放该抗原。 将尝试治疗操作来加载和敏化基质。如果癌细胞表达太少 为了使基质敏感，将尝试用外源性抗原加载基质。最后通过 通过窗口开口对已确定的大肿瘤进行光学成像， 将分析过继转移的T细胞遇到癌细胞和癌基质时发生的变化。 这可能揭示了过继转移的T细胞破坏大的已建立的肿瘤的主要靶点， 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瘤 在病人身上可以检测到，甚至在啮齿动物身上也能逃脱常规的免疫治疗。的 计划是建立原则和开发新的方法作为指导发展的小说 治疗以根除患者中已建立的实体瘤。

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.