Mechanisms of Concomitant Tumor Immunity

描述（由申请人提供）：伴随性肿瘤免疫是肿瘤进行性宿主对远端同一肿瘤的免疫排斥反应。这种肿瘤引发的T细胞介导的保护以前被认为只发生在高免疫原性肿瘤中。然而，我们最近发现，对低免疫原性肿瘤的伴随免疫可以通过调节性T细胞（Tregs）的消耗来诱导。拟议的研究将描述控制伴随免疫的诱导、维持和抑制的机制。这项研究将采用一种与人类疾病非常相似的低免疫原性小鼠黑色素瘤模型。这一提议将验证一种假设，即进行性、免疫原性差的肿瘤有能力指导对癌症的持久免疫。特异性目标1将确定原发肿瘤手术切除后伴随免疫维持的机制。研究将描述切除后对局部和转移性黑色素瘤的长期保护。这种保护作用将与肿瘤诱导的中枢和效应记忆T细胞对多种黑色素瘤表达的自身抗原的反应有关。特异性目标2将定义诱导最佳伴随免疫的机制。通过GITR（糖皮质激素诱导的TNFR家族相关蛋白）刺激各种T细胞群，以及给予淋巴消耗化疗，将被研究作为驱动肿瘤宿主中CD8+效应和CD4+辅助T细胞激活和增殖的方法。通过监测伴随免疫，这些研究将揭示保护性免疫反应的产生，否则在荷瘤宿主中仍未被发现。特异性目的3将确定肿瘤抑制伴随免疫的机制。研究将依靠表达Foxp3-GFP报告基因的转基因小鼠来精确表征荷瘤小鼠的Tregs。结果表明，进展性、低免疫原性黑色素瘤诱导treg的启动和扩增，这些treg对肿瘤表达的自身抗原具有特异性。总的来说，拟议的研究将确定在不使用主动免疫（疫苗）的情况下，在携带免疫原性较差的肿瘤的宿主中产生持久的T细胞介导免疫的机制。这些研究有望证明，在肿瘤生长过程中操纵宿主自身的免疫环境足以诱导对复发和转移性疾病的长期保护。

DESCRIPTION (provided by applicant): Concomitant tumor immunity is the response whereby a host with a progressive tumor rejects an inoculum of the same tumor at a distal site. This tumor-primed, T cell-mediated protection was previously thought to occur only with highly-immunogenic tumors. However, we have recently found that concomitant immunity to poorly-immunogenic tumors can be induced by the depletion of regulatory T cells (Tregs). The proposed studies will characterize the mechanisms that govern the induction, maintenance, and suppression of concomitant immunity. This research will employ a poorly-immunogenic mouse melanoma model that closely resembles human disease. This proposal will test the hypothesis that progressive, poorly-immunogenic tumors have the capacity to instruct durable immunity to cancer. Specific Aim 1 will identify mechanisms for the maintenance of concomitant immunity following the surgical excision of primary tumors. Studies will characterize long-term post-excisional protection against local and metastatic melanoma. Protection will be correlated with the tumor-induced priming of central and effector memory T cell responses against multiple melanoma-expressed self antigens. Specific Aim 2 will define the mechanisms whereby optimum concomitant immunity is induced. The stimulation of various T cell populations through GITR (glucocorticoid-induced TNFR family-related protein), as well as the administration of lymphodepleting chemotherapy will be investigated as methods for driving activation and proliferation of CD8+ effector and CD4+ helper T cells in tumor-bearing hosts. By monitoring concomitant immunity, these studies will reveal the generation of protective immune responses that would otherwise remain undetected in tumor-bearing hosts. Specific Aim 3 will define mechanisms whereby tumors suppress concomitant immunity. Studies will rely on transgenic mice expressing a Foxp3-GFP reporter gene to enable the precise characterization of Tregs in tumor-bearing mice. Results are expected to demonstrate that progressive, poorly-immunogenic melanoma induces priming and expansion of Tregs that are specific for tumor-expressed self antigens. Collectively, the proposed studies will define mechanisms for generating durable, T cell-mediated immunity in hosts bearing poorly-immunogenic tumors, without the use of active immunization (vaccines). These studies are expected to demonstrate that manipulating the host's own immune milieu during tumor growth is sufficient for inducing long-lived protection against recurrent and metastatic disease. Surgery is currently the most successful treatment for solid tumors. However, patients continue to succumb to metastatic disease. This research is expected to lead to therapies which will utilize patients' own immune systems to prevent the recurrence and metastasis of cancers following surgery.