A Pull-Push Strategy for Lymphoma Immunotherapy

描述（由申请人提供）：尽管目前人类淋巴瘤的多模式治疗可以诱导高完全缓解率，但大多数患者最终复发且无法治愈。因此，挑战在于开发更有效的策略，新的免疫治疗方式代表着一个有希望的领域。对肿瘤的免疫耐受和缺乏明确的肿瘤抗原是发展有效的癌症免疫治疗的两大障碍。树突状细胞是最有效的抗原呈递细胞。最近令人信服的数据表明，dc及其与调节性T细胞（Treg）的相互作用在免疫自我耐受的产生和维持中起着关键作用。CD4+CD25+ treg对自身免疫性疾病的预防至关重要。快速积累的数据，包括我们的初步数据，为浸润性癌症患者的肿瘤微环境和外周血中CD4+CD25+ Treg细胞的患病率增加提供了证据，表明这些细胞在肿瘤免疫监测中具有潜在的负面作用。

DESCRIPTION (provided by applicant): Despite the fact that current multi-modality treatment of human lymphomas can induce a high rate of complete remission, the majority of patients ultimately relapse and cannot be cured. The challenge, then, is to develop more effective strategies, with new immunotherapy modalities representing a promising area. Immunological tolerance to tumors and the lack of defined tumor antigens are the two major hurdles for the development of effective cancer immunotherapy. Dendritic cells (DCs) are the most potent antigen presenting cells. Recent compelling data suggest that DCs and their interaction with regulatory T cells (Treg) play critical roles in the generation and maintenance of immunologic self-tolerance. CD4+CD25+ Tregs are crucial for the prevention of autoimmune diseases. Rapidly accumulating data, including our preliminary data, provide evidence for an increased prevalence of CD4+CD25+ Treg cells in the tumor microenvironment and in the peripheral blood of patients with invasive cancers, indicating a potential negative role by these cells in tumor immunosurveillance. This proposal focuses on lymphoma immunotherapy and will address the two hurdles, and presents a plan to develop strategies to overcome these hurdles. The first hypothesis is that DCs are present in situ in the tumor, but are maintained in an inactive state either by regulatory T cells (CD4+CD25+) or by tumor cells, thereby leading to immunological tolerance to tumor antigens. Therefore effective immune responses to lymphomas do not occur naturally in patients with the tumors. The second hypothesis is that tumor antigens released by dying tumor cells after chemo- or radiation therapy are not efficiently cross-presented in vivo by DCs, due to either DC dysfunction or limited DC number in situ. Therefore systemic immune responses to lymphomas are not efficiently induced after chemo- or radiation therapy in patients with lymphomas. The major focus of this proposal is to characterize CD4+CD25+ regulatory T cells in human lymphomas, and to develop strategies in mouse models to counteract Treg cells (Pull) before delivering ex vivo expanded DCs to tumor sites (Push) after chemotherapy or local radiation therapy. The goal is to enhance cross-presentation of potential tumor antigens in vivo (Pull-Push strategy) and thus to induce systemic anti-tumor immunity and to eliminate the residual tumor. Hopefully these studies will pave the way for novel immunotherapy strategies which will be tested in future human clinical trials.