ENHANCEMENT OF ANTI-TUMOR IMMUNOTHERAPIES

描述（由申请人提供）：肿瘤抗原和特异性抗肿瘤免疫反应的发现为肿瘤的免疫治疗带来了希望。然而，动物模型和临床试验强烈表明，抗肿瘤免疫反应在肿瘤宿主中是耐受的。这种耐受性可通过多种与肿瘤产物、抑制细胞和血清抑制因子相关的免疫抑制作用介导。因此，免疫治疗的努力，特别是那些用肿瘤疫苗对患者进行免疫的努力，必须与这种免疫抑制作斗争，以获得有效的抗肿瘤免疫反应来消除肿瘤。我们的初步研究表明，许多人和小鼠肿瘤细胞表达神经元排斥狭缝，一组抑制白细胞迁移的分子。我们实验室最近的研究表明，裂缝抑制树突状细胞的迁移和抑制免疫反应。白细胞不能浸润肿瘤是一个共同的特征。令人信服的数据表明，肿瘤中的白细胞浸润与患者的预后有关，是免疫治疗临床反应的指示性参数。我们的假设是，阻断肿瘤源性狭缝会增强免疫细胞在肿瘤中的浸润，提高抗肿瘤免疫治疗的效率。这一假设将在三个具体目标中进行检验。(1)检测人类肿瘤中狭缝的产生和活性。该结果将为Slit介导的免疫抑制在肿瘤患者中的作用提供证据。(2)探讨肿瘤源性狭缝在诱导抗肿瘤免疫应答中的作用。该目的将确定阻断狭缝是否会破坏肿瘤介导的免疫抑制，从而诱导免疫应答，并提高肿瘤疫苗接种的效率。(3)确定裂隙在肿瘤免疫治疗排斥反应中的作用。我们将通过树突状细胞免疫疗法和免疫T细胞过继性转移来研究阻断肿瘤来源的狭缝是否能改善已建立肿瘤的排斥反应。该建议的最终目标是确定肿瘤衍生狭缝作为肿瘤免疫治疗发展的新靶点，并建立增强抗肿瘤免疫反应的方案。该结果可能为提高肿瘤免疫治疗的效率和临床反应提供有价值的信息。

DESCRIPTION (provided by applicant): The discovery of tumor antigens and specific anti-tumor immune responses has raised hopes for the immunotherapy of tumors. However, animal models as well as clinical trials strongly suggest that the anti-tumor immune response is tolerized in a tumor-bearing host. The tolerance can be mediated by a variety of immunosuppressive effects relating to tumor products, suppressor cells and serum suppressive factors. Therefore, immunotherapy efforts, particular those to immunize patients with tumor vaccines, have to contend with this immunosuppression in order to obtain efficient anti-tumor immune responses to eliminate tumors. Our preliminary studies indicate that many human and mouse tumor cells express neuronal repellent Slits, a group of molecules that inhibit leukocyte migration. Recent studies in our laboratory have indicated that Slits inhibit the migration of dendritic cells and suppress immune responses. It is a common feature that leukocytes fail to infiltrate tumors. Convincing data exhibit that leukocyte infiltration in tumors is associated with the prognosis of patients and is an indicative parameter for the clinical response of immunotherapy. Our hypothesis is that blocking tumor derived Slits will enhance the infiltration of immune cells in tumors and improve the efficiency of anti-tumor immunotherapy. The hypothesis will be examined in three specific aims. (1) To detect the production and activity of Slits in human tumors. The result will provide evidence for the effect of Slit mediated immunosuppression in tumor patients. (2) To examine the role of tumor derived Slits in the induction of anti-tumor immune responses. This aim will identify whether blocking Slits breaks down tumor mediated immunosuppression on the induction of immune responses and enhances the efficiency of tumor vaccination. (3) To determine the effect of Slits in the rejection of established tumors by immunotherapies. We will examine whether blocking tumor derived Slits improves the rejection of established tumors by dendritic cell based immunotherapy and adoptive transfer of immune T cells. The ultimate goal of the proposal is to identify tumor derived Slits as a new target in the development of tumor immunotherapy and to establish protocols for enhancement of anti-tumor immune responses. The outcome may provide valuable information for improving the efficiency and clinical response of tumor immunotherapies.