Mechanisms of Concomitant Tumor Immunity

描述（由申请方提供）：伴随肿瘤免疫是一种反应，其中患有进展性肿瘤的宿主排斥远端部位相同肿瘤的接种物。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，伴随免疫性差的免疫原性肿瘤可以诱导的调节性T细胞（Tcells）的耗竭。拟定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免疫原性差的小鼠黑色素瘤模型，该模型与人类疾病非常相似。这项提议将检验进行性、免疫原性差的肿瘤有能力指导对癌症的持久免疫的假设。具体目标1将确定原发性肿瘤手术切除后维持伴随免疫的机制。研究将描述长期切除后对局部和转移性黑色素瘤的保护作用。保护将与肿瘤诱导的针对多种黑素瘤表达的自身抗原的中枢和效应记忆T细胞应答的引发相关。具体目标2将定义诱导最佳伴随免疫的机制。将研究通过GITR（糖皮质激素诱导的TNFR家族相关蛋白）刺激各种T细胞群以及淋巴细胞清除化疗的给药，作为驱动荷瘤宿主中CD 8+效应T细胞和CD 4+辅助T细胞活化和增殖的方法。通过监测伴随免疫，这些研究将揭示保护性免疫应答的产生，否则这些免疫应答在荷瘤宿主中将无法检测到。具体目标3将定义肿瘤抑制伴随免疫的机制。研究将依赖于表达Foxp 3-GFP报告基因的转基因小鼠，以精确表征荷瘤小鼠中的TcB。预期结果表明，进行性、免疫原性差的黑色素瘤诱导对肿瘤表达的自身抗原具有特异性的TcR的引发和扩增。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，在携带免疫原性差的肿瘤的宿主中产生持久的T细胞介导的免疫的机制。这些研究有望证明，在肿瘤生长期间操纵宿主自身的免疫环境足以诱导针对复发性和转移性疾病的长期保护。 手术是目前治疗实体瘤最成功的方法。然而，患者继续死于转移性疾病。这项研究有望开发出利用患者自身免疫系统预防手术后癌症复发和转移的疗法。

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.