The role of Albumin-Flt3L-induced cross-presenting dendritic cell expansion in antitumor immunity

项目总结/摘要 能够在广泛的癌症类型中介导抗肿瘤反应的癌症治疗策略仍然存在 即使随着新的免疫治疗剂如检查点阻断的快速发展，也是有限的。的 癌症的巨大公共卫生负担产生了对新颖的、广泛有效的 免疫治疗基本上所有癌症治疗策略的成功的核心是产生 肿瘤特异性细胞毒性CD 8 + T细胞免疫，其需要树突状细胞的有效抗原呈递 (DCs)因为肿瘤细胞不能有效地呈递相关的CD 8 + T细胞表位。DC必须摄取肿瘤细胞 或肿瘤抗原和交叉呈递免疫刺激肽至CD 8 + T细胞。然而，发展中国家的数量 亚群，和大多数执行低于标准杆交叉介绍。已知CD 103+和CD 8a + DC以其特异性结合而存在。 处理外源抗原并有效地交叉呈递给CD 8 + T细胞的能力。正因为如此， 增强的交叉呈递DC亚群可能在许多癌症类型的治疗中具有治疗潜力。 FMS样酪氨酸激酶3配体（Flt 3L）是一种细胞因子，其扩增和分化DC前体以交叉配体。 Flt 3L可提呈CD 103+和CD 8a + DC，但由于其半衰期短，其治疗潜力有限 和体内的全球分布。我们已经通过产生基因融合体克服了Flt 3L的所述问题， 将白蛋白（Alb）转化为Flt 3L，命名为白蛋白-Flt 3L（Alb-Flt 3L）。由于新生儿Fc受体，Alb具有较长的半衰期- （FcRn）介导的转细胞再循环，并表现出作为普遍存在的血清运输到淋巴系统 蛋白新型免疫治疗剂Alb-Flt 3L融合蛋白具有延长的半衰期和选择性 与天然Flt 3L相比，在引流淋巴结中的累积。Alb-Flt 3L能够扩展交叉- 在体内提呈DC群，并因此产生有效的抗原特异性CD 4+和CD 8 + T细胞 和蛋白免疫后的B细胞应答。在这项研究中，Alb-Flt 3L诱导抗原的能力， 通过交叉提呈DC的扩增和随后的肿瘤控制产生特异性抗肿瘤免疫， 追究结肠腺癌的小鼠模型和HPV相关癌症的待治疗模型 使用Alb-Flt 3L与靶向放射治疗组合以释放肿瘤抗原并增强细胞增殖， 磁导率随后的抗肿瘤CD 4+和CD 8 + T细胞和交叉呈递DC免疫应答， 将评价肿瘤控制。Alb-Flt 3L介导其免疫刺激功能的机制 还将使用适当的缺陷小鼠模型进行询问。成功完成此提案将 产生关于Alb-Flt 3L的治疗潜力的有价值的临床前和机制数据， 具有潜在功效的免疫疗法作为治疗多种类型癌症的通用策略。拟议 研究金申请人将在赞助下进行为期3年的研究， T博士的指导- C.约翰霍普金斯大学医学院的吴博士说。调查结果将作为 国家会议的摘要以及在研究金培训期结束前出版。

Project Summary/Abstract Cancer treatment strategies capable of mediating antitumor response in a wide array of cancer types remain limited, even with the rapid development of novel immunotherapeutics such as checkpoint blockade. The overwhelming public health burden of cancer has created great demand for novel, broadly effective immunotherapeutics. Central to the success of essentially all cancer treatment strategies is the generation of tumor specific cytotoxic CD8+ T cell immunity, which requires potent antigen presentation by dendritic cells (DCs) since tumor cells do not efficiently present relevant CD8+ T cell epitopes. DCs must uptake tumor cells or tumor antigen and cross-present immunostimulatory peptides to CD8+ T cells. However, DCs exist as many subpopulations, and most perform subpar cross-presentation. CD103+ and CD8a+ DCs are known for their ability to process exogenous antigen and potently cross-present to CD8+ T cells. Because of this, strategies to enhance cross-presenting DC subsets could have therapeutic potential in the treatment of many cancer types. FMS-like tyrosine kinase 3 ligand (Flt3L) is a cytokine that expands and differentiates DC precursors to cross- presenting CD103+ and CD8a+ DCs, but therapeutic potential of Flt3L is limited because of its short half-life and global distribution in vivo. We have overcome the described issues of Flt3L by generating a genetic fusion of Albumin (Alb) to Flt3L named Albumin-Flt3L (Alb-Flt3L). Alb has a long half-life due to neonatal Fc receptor- (FcRn)-mediated transcytolic recycling, and exhibits trafficking to the lymphatic system as a ubiquitous serum protein. The novel immunotherapeutic Alb-Flt3L fusion protein exhibits increased half-life and selective accumulation in the draining lymph node compared to native Flt3L. Alb-Flt3L is able to expand cross- presenting DC populations in vivo, and consequently engenders potent antigen specific CD4+ and CD8+ T cell and B cell responses following protein immunization. In this study, the ability of Alb-Flt3L to induce antigen specific antitumor immunity through the expansion of cross-presenting DCs and subsequent tumor control will be investigated. Murine model of colon adenocarcinoma and model of HPV-associated cancer with be treated using Alb-Flt3L in combination with targeted radiation therapy to release tumor antigen and enhance cellular permeability. Subsequent antitumor CD4+ and CD8+ T cell and cross-presenting DC immune responses and tumor control will be evaluated. The mechanism by which Alb-Flt3L mediates its immunostimulatory function will also be interrogated using appropriate deficient mouse models. Successful completion of this proposal will generate valuable preclinical and mechanistic data regarding the therapeutic potential of Alb-Flt3L, a novel immunotherapeutic with potential efficacy as a universal strategy to treat many types of cancer. The proposed research will be conducted over a period of 3 years by the fellowship applicant under the sponsorship and guidance of Dr. T.-C. Wu at the Johns Hopkins University School of Medicine. The findings will be submitted as abstracts to national meetings as well as for publication prior to the end of the fellowship training period.