Mechanisms of Concomitant Tumor Immunity

描述(申请人提供)：伴随的肿瘤免疫是一种反应，患有进展性肿瘤的宿主排斥同一肿瘤远端接种。这种肿瘤启动的T细胞介导的保护以前被认为只发生在高度免疫原性的肿瘤中。然而，我们最近发现，对免疫原性低的肿瘤的伴随免疫可以通过耗尽调节性T细胞(Tregs)来诱导。拟议的研究将描述诱导、维持和抑制伴随免疫的机制。这项研究将采用一种免疫原性较差的小鼠黑色素瘤模型，该模型与人类疾病非常相似。这项提议将检验这样一种假设，即进行性的、免疫原性差的肿瘤有能力指示对癌症的持久免疫。具体目标1将确定手术切除原发肿瘤后维持伴随免疫的机制。研究将表征切除后对局部和转移性黑色素瘤的长期保护作用。保护将与肿瘤诱导的中枢和效应性记忆T细胞对多种黑色素瘤表达的自身抗原的反应相关。具体目标2将确定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)刺激不同的T细胞群，以及淋巴清除化疗的实施，将被研究为在荷瘤宿主中驱动CD8+效应T细胞和CD4+辅助T细胞的激活和增殖的方法。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，否则这些免疫反应在荷瘤宿主中仍未被检测到。具体目标3将确定肿瘤抑制伴随免疫的机制。研究将依赖于表达Foxp3-GFP报告基因的转基因小鼠，以便能够在荷瘤小鼠中精确描述Tregs。研究结果有望证明，进行性、免疫原性差的黑色素瘤可以诱导肿瘤表达的自身抗原特异的Tregs的启动和扩张。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对复发和转移性疾病的长期保护。 手术是目前治疗实体肿瘤最成功的方法。然而，患者继续死于转移性疾病。这项研究有望带来利用患者自身免疫系统防止癌症手术后复发和转移的治疗方法。

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.