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

白蛋白-Flt3L诱导的交叉呈递树突状细胞扩增在抗肿瘤免疫中的作用

• 批准号: 10049239
• 负责人: Brandon Krishna Lam
• 金额: $ 3.72万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-06 至 2021-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10049239
• 关键词: Adjuvant; Albumins; Animals; Antigen Presentation; Antigens; Antitumor Response; B-Lymphocytes; Binding; Biological; Bone Marrow; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CXCL10 gene; CXCL9 gene; Cancer Burden; Cancer Model; Cells; Chimeric Proteins; Colon Adenocarcinoma; Cross Presentation; Data; Dendritic Cells; Destinations; Development; Excision; Exhibits; FLT3 ligand; Face; Fc Receptor; Fellowship; Future; Gene Expression; Generations; Genetic; Half-Life; Human Papilloma Virus-Related Malignant Neoplasm; Immune response; Immunity; Immunization; Immunologic Memory; Immunotherapeutic agent; Immunotherapy; Inflammatory; Injections; Interferon-alpha; Interferon-beta; Knockout Mice; Leucine Zippers; Ligands; Low Dose Radiation; Lymphatic System; MC38; Measures; Mediating; Memory; Modeling; Mus; Names; Operative Surgical Procedures; Peptides; Permeability; Physiological; Play; Population; Process; Production; Proteins; Public Health; Publications; Radiation; Radiation therapy; Recycling; Research; Role; Serum Proteins; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Epitopes; Therapeutic; Therapeutic Uses; Training; Transcription Factor 3; Tumor Antigens; Tumor Immunity; Tumor-infiltrating immune cells; Universities; activating transcription factor; adaptive immunity; anti-tumor immune response; antigen-specific T cells; bZIP Domain; cancer therapy; cancer type; chemokine; chemotherapy; clinical efficacy; cytokine; cytotoxic CD8 T cells; cytotoxicity; digital; draining lymph node; fetal liver kinase-2; immune checkpoint blockade; in vivo; inflammatory milieu; intravenous administration; lymph nodes; medical schools; meetings; mouse model; neoantigens; neonatal Fc receptor; neoplastic cell; novel; pre-clinical; progenitor; response; success; tool; trafficking; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor progression; uptake

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.

项目概要/摘要 能够在多种癌症类型中介导抗肿瘤反应的癌症治疗策略仍然存在 即使检查点封锁等新型免疫疗法快速发展，但其作用仍然有限。这 癌症带来的巨大公共卫生负担创造了对新型、广泛有效的药物的巨大需求 免疫治疗。基本上所有癌症治疗策略成功的核心是产生 肿瘤特异性细胞毒性 CD8+ T 细胞免疫，需要树突状细胞提供有效的抗原 (DC)，因为肿瘤细胞不能有效地呈现相关的 CD8+ T 细胞表位。 DCs必须摄取肿瘤细胞 或肿瘤抗原并将免疫刺激肽交叉呈递给 CD8+ T 细胞。然而，DC 存在很多 亚群体，并且大多数人的交叉表现不佳。 CD103+ 和 CD8a+ DC 以其 处理外源抗原并有效交叉呈递给 CD8+ T 细胞的能力。正因为如此，策略 增强交叉呈递的 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 (Flt3L) 是一种细胞因子，可扩展和分化 DC 前体以进行交叉 呈递 CD103+ 和 CD8a+ DC，但 Flt3L 的治疗潜力因其半衰期短而受到限制 和体内的全球分布。我们通过生成基因融合克服了 Flt3L 的上述问题 白蛋白 (Alb) 转化为 Flt3L，命名为白蛋白-Flt3L (Alb-Flt3L)。由于新生儿 Fc 受体，Alb 的半衰期很长 - (FcRn) 介导的跨细胞再循环，并以普遍存在的血清形式运输至淋巴系统 蛋白质。新型免疫治疗 Alb-Flt3L 融合蛋白表现出半衰期延长和选择性 与天然 Flt3L 相比，引流淋巴结中的积累。 Alb-Flt3L 能够扩展交叉 在体内呈递 DC 群体，从而产生有效的抗原特异性 CD4+ 和 CD8+ T 细胞 和蛋白质免疫后 B 细胞的反应。在本研究中，Alb-Flt3L诱导抗原的能力 通过交叉呈递 DC 的扩增和随后的肿瘤控制将产生特异性抗肿瘤免疫 被调查。小鼠结肠腺癌模型和待治疗的HPV相关癌症模型 使用Alb-Flt3L结合靶向放射治疗释放肿瘤抗原并增强细胞 渗透性。随后的抗肿瘤 CD4+ 和 CD8+ T 细胞以及交叉呈递的 DC 免疫反应和 将评估肿瘤控制。 Alb-Flt3L介导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。本提案的顺利完成将 生成有关 Alb-Flt3L（一种新型药物）治疗潜力的有价值的临床前和机制数据 免疫疗法作为治疗多种癌症的通用策略具有潜在功效。拟议的 奖学金申请人将在赞助下进行为期 3 年的研究，并且 T.-C 博士的指导。吴在约翰霍普金斯大学医学院。调查结果将提交为 摘要提交给国家会议并在研究金培训期结束前出版。

项目成果

Profiling of VEGF Receptors and Immune Checkpoints in Recurrent Respiratory Papillomatosis.

复发性呼吸道乳头状瘤病中 VEGF 受体和免疫检查点的分析。

• DOI: 10.1002/lary.31253
• 发表时间: 2024
• 期刊: The Laryngoscope
• 作者: Lam,Brandon;Miller,Jonas;Kung,YuJui;Wu,TC;Hung,Chien-Fu;Roden,RichardBS;Best,SimonR
• 通讯作者: Best,SimonR

Localization of Salmonella and albumin-IL-2 to the tumor microenvironment augments anticancer T cell immunity.

• DOI: 10.1186/s12929-022-00841-y
• 发表时间: 2022-08-12
• 期刊: JOURNAL OF BIOMEDICAL SCIENCE
• 影响因子: 11
• 作者: Kung, Yu-Jui;Lam, Brandon;Tseng, Ssu-Hsueh;MacDonald, Alana;Tu, Hsin-Fang;Wang, Suyang;Lin, John;Tsai, Ya Chea;Wu, T. C.;Hung, Chien-Fu
• 通讯作者: Hung, Chien-Fu