Radiotherapy as Immunotherapy of Tumors

描述（由申请人提供）：我们的初步研究表明，对小鼠结肠或乳腺肿瘤进行单次高剂量辐射或高剂量低分割辐射可诱导完全缓解以及全身抗肿瘤免疫，这种免疫可通过T细胞转移。T细胞是肿瘤缓解所必需的。本课题的目标是确定转移后脾和淋巴结中介导抗肿瘤免疫的T细胞亚群，确定肿瘤中的T细胞是否存在免疫缺陷，无法转移抗肿瘤活性，肿瘤中的免疫抑制细胞是否能够干扰这种转移。此外，我们将通过研究肿瘤产生的趋化因子和T细胞上能够浸润肿瘤的趋化因子受体，来确定放疗后T细胞向肿瘤迁移的分子基础。最后，我们将确定在存在或不存在来自肿瘤患者的注射T细胞的情况下，在免疫缺陷小鼠中生长的人类胰腺肿瘤是否可以通过辐射诱导其消退。提出的实验使用染色和流式细胞术来鉴定和纯化用于转移研究和肿瘤浸润细胞分析的免疫细胞。基因修饰小鼠被用来阐明抗肿瘤T细胞介导释放和运输到肿瘤的关键效应分子。拟议的研究旨在为未来的临床方案提供模型，这些方案可以使用立体定向身体辐射（SBRT）与化疗和自体T细胞治疗相结合，以增强当前放疗和化疗联合治疗癌症的效力。

DESCRIPTION (provided by applicant): Our Preliminary Studies show that a single high dose of radiation or high doses of hypofractionated radiation administered to colon or breast tumors in mice can induce complete remissions as well as systemic anti-tumor immunity that is transferable with T cells. The T cells are required for tumor remissions. The goals of the current proposal are to determine the subsets of T cells in the spleen and lymph nodes that mediate anti-tumor immunity after transfer, and to determine whether T cells in tumors are immunodeficient and unable to transfer anti-tumor activity, and whether immune suppressor cells in the tumor can interfere with the transfer. In addition, we will determine the molecular basis of T cell migration to the tumors after radiotherapy by investigating chemokines produced by the tumors and chemokine receptors on the T cells that can infiltrate tumors. Finally, we will determine whether human pancreas tumors growing in immunodeficient mice can be induced to regress by radiation in the presence or absence of injected T cells from the tumor bearing patients. The proposed experiments use staining and flow cytometry to identify and purify immune cells for transfer studies and for analysis of tumor infiltrating cells. Gene modified mice are used to elucidate the key effector molecules used by anti-tumor T cells to mediate remissions and to traffic to tumors. The proposed studies are designed to be models for future clinical protocols that can use stereotactic body radiation (SBRT) in combination with chemotherapy and autologous T cell therapy to enhance the potency of current combinations of radiotherapy and chemotherapy to treat cancer. PUBLIC HEALTH RELEVANCE: Our Preliminary Studies showed that a single high of radiation to colon or breast tumors in mice can induce complete remissions as well as systemic anti-tumor immunity that is transferable with immune cells called T cells. The T cells are required for remissions. The proposed studies will determine the types of T cells that induce remissions, whether tumors contain cells that can suppress the transfer of anti-tumor activity, and whether human pancreas cancers growing in mice can be induced to regress in the presence or absence of injected T cells from the cancer patients.