Nucleus Accumbens-Associated Protein-1 in Melanoma Immunotherapy

黑色素瘤免疫治疗中的伏核相关蛋白 1

基本信息

批准号：
10519108
负责人：
Jianxun Jim Song
金额：
$ 55.06万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-03 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10519108
关键词：
Adoptive Cell Transfers Affect Antigens Autophagocytosis Biological Models CD8-Positive T-Lymphocytes CTLA4 gene Cancer Biology Cells Cessation of life Clinical Cytotoxic T-Lymphocytes Development Disease FASN gene Gene Expression Gene Family Genes Genetic Transcription Glycolysis Goals Immune Immune checkpoint inhibitor Immune response Immunity Immunology Immunosuppression Immunosuppressive Agents Immunotherapy In Vitro Induction of Apoptosis Laboratories Literature Major Histocompatibility Complex Malignant Neoplasms Mediating Melanoma Cell Memory Metabolic Metabolism Metastatic Melanoma Modeling Molecular Mus Myeloid-derived suppressor cells Neoplasms Nucleus Accumbens Oncogenic Outcome Patients Play Pluripotent Stem Cells Proteins Publishing Recurrent Malignant Neoplasm Refractory Regulation Regulatory T-Lymphocyte Role Skin Cancer Small Interfering RNA T memory cell T-Cell Development T-Lymphocyte Testing Therapeutic Tumor Antigens Tumor Immunity Tumor-associated macrophages cancer recurrence cancer type cytokine cytotoxic CD8 T cells design effector T cell gene product human pluripotent stem cell immunogenicity improved improved outcome in vivo Model innovation melanoma nanoliposome negative affect neoantigens neoplastic cell novel novel strategies novel therapeutics nutrition programmed cell death ligand 1 programmed cell death protein 1 resilience response therapy outcome tumor tumor immunology tumor microenvironment tumor-immune system interactions

项目摘要

PROJECT SUMMARY/ABSTRACT As melanoma mostly expresses tumor-specific neo-antigens (Ags), immunotherapy such as adoptive cell transfer-based therapy (ACT) is considered a promising treatment option for this notoriously deadly disease. Nevertheless, due to various factors that may weaken therapeutic immunity, the clinical outcomes and benefits of this remedy remain less satisfactory. Importantly, accumulating evidence suggests that the metabolic status of both immune cells and tumor cells has a significant impact on the potency of ACT, and that metabolic reprogramming may represent a viable target for reinforcing immunotherapy. Nucleus accumbens-associated protein-1 (NAC1) is a transcription co-regulator belonging to the BTB/POZ gene family, and is highly expressed in several types of cancer including melanoma. Published studies including our own have shown that NAC1 not only bestows oncogenic potential but also undermines therapeutic outcomes through its transcription- dependent or -independent functions. More recently, we discovered that NAC1 can promote glycolysis through its interaction with HIF-1a, and is critically required for development, survival and function of T cells as well as tumor cells. We also found that NAC1 negatively affects the tumoral expression of major histocompatibility complexes (MHCs); the alteration of NAC1 gene expression occurs during differentiation of the pluripotent stem cell (PSC)-derived T cells, and this alteration is accompanied by changes in the expressions of a number of other genes. Based on these intriguing findings, we hypothesize that NAC1-mediated metabolic reprogramming suppresses anti-tumor immunity; targeting NAC1 would hasten death or reduce resilience of both tumor and suppressor immune cells and modulate the expression of tumor Ags, checkpoint molecules and the related proteins, thereby relieving immune-suppression and reinforcing the efficacy of ACT against melanoma. To test these hypotheses, the current multiple PI application proposes the following highly interactive specific aims: (1) To determine the novel role of NAC1 in T cells; (2) To determine the role of tumoral NAC1 in melanoma immune escape; and (3) To determine the impact of targeting NAC1 in ACT against melanoma. This multiple PI project combines the Yang laboratory’s strength in cancer biology with the Song laboratory’s expertise in tumor immunology. We have already established the mouse and human PSC- derived antigen-specific CD8+ T lymphocytes, and the murine syngeneic and humanized (NOD-scid IL2rgnull) mouse melanoma models for the proposed studies, and are well poised to accomplish the above aims. Completion of this project will not only uncover NAC1 as a unique molecular determinant of tumor-specific immune responses and shed new light on the importance of NAC1 in cancer pathobiology, but also provide novel therapeutic opportunities to enhance ACT against melanoma through the NAC1-targeted strategy.

项目概要/摘要由于黑色素瘤大多表达肿瘤特异性新抗原（Ags），因此过继细胞等免疫疗法基于转移的治疗（ACT）被认为是治疗这种众所周知的致命疾病的一种有前途的治疗选择。然而，由于多种因素可能削弱治疗免疫力，临床结果和益处重要的是，越来越多的证据表明这种疗法的效果仍然不太令人满意。免疫细胞和肿瘤细胞的代谢对 ACT 的效力有显着影响，并且代谢重编程可能是加强伏隔核相关免疫治疗的一个可行靶点。 Protein-1 (NAC1) 是一种转录共调节因子，属于 BTB/POZ 基因家族，并且高度表达已发表的研究（包括我们自己的研究）已表明 NAC1 在包括黑色素瘤在内的多种癌症中发挥作用。不仅具有致癌潜力，而且还通过其转录破坏治疗结果最近，我们发现 NAC1 可以通过促进糖酵解。它与 HIF-1a 相互作用，是 T 细胞的发育、存活和功能所必需的我们还发现 NAC1 对主要组织相容性的肿瘤表达产生负面影响。复合体 (MHC)；NAC1 基因表达的改变发生在多能分化过程中干细胞 (PSC) 衍生的 T 细胞，这种改变伴随着许多表达的变化基于这些有趣的发现，我们发现了 NAC1 介导的代谢。重编程会抑制抗肿瘤免疫；针对 NAC1 会加速死亡或降低细胞的恢复能力肿瘤和抑制性免疫细胞并调节肿瘤抗原、检查点分子的表达和相关蛋白，从而缓解免疫抑制并增强 ACT 的功效为了检验这些假设，当前的多重 PI 应用提出了以下高度建议：互动具体目标： (1) 确定 NAC1 在 T 细胞中的新作用； (2) 确定 NAC1 在 T 细胞中的作用；肿瘤 NAC1 在黑色素瘤免疫逃逸中的作用；以及 (3) 确定靶向 NAC1 在 ACT 中的影响这个多重 PI 项目将杨实验室在癌症生物学方面的优势与宋实验室在肿瘤免疫学方面的专业知识我们已经建立了小鼠和人类PSC-。衍生的抗原特异性 CD8+ T 淋巴细胞，以及鼠同基因和人源化 (NOD-scid IL2rgnull) 小鼠黑色素瘤模型用于拟议的研究，并且已经做好了实现上述目标的准备。该项目的完成不仅将揭示 NAC1 作为肿瘤特异性的独特分子决定因素免疫反应并为 NAC1 在癌症病理学中的重要性提供了新的线索，同时也提供了通过 NAC1 靶向策略增强 ACT 对抗黑色素瘤的新治疗机会。

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma.

胰腺导管腺癌免疫治疗的最新进展和展望。

DOI：
发表时间：
2020
期刊：
影响因子：
37.3
作者：
Fan, Jia;Wang, Meng;Chen, Hai;Shang, Dong;Das, Jugal K;Song, Jianxun
通讯作者：
Song, Jianxun

Metabolic Reprogramming and Reactive Oxygen Species in T Cell Immunity.

T 细胞免疫中的代谢重编程和活性氧。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Peng, Hao;Lucavs, Jason;Ballard, Darby;Das, Jugal Kishore;Kumar, Anil;Wang, Liqing;Ren, Yijie;Xiong, Xiaofang;Song, Jianxun
通讯作者：
Song, Jianxun

SET domain containing 1B gene is mutated in primary hepatic neuroendocrine tumors.

含有1B基因的SET结构域在原发性肝神经内分泌肿瘤中发生突变。

DOI：
发表时间：
2019
期刊：
影响因子：
6.4
作者：
Yang, Penghui;Huang, Xuanlin;Lai, Chengcai;Li, Lin;Li, Tieling;Huang, Peide;Ouyang, Songying;Yan, Jin;Cheng, Sijie;Lei, Guanglin;Wang, Zhaohai;Yu, Linxiang;Hong, Zhixian;Li, Ruisheng;Dong, Hui;Wang, Cheng;Yu, Yinghao;Wang, Xuan;Li, Xiang
通讯作者：
Li, Xiang

Targeting Stem Cell-Derived Tissue-Associated Regulatory T Cells for Type 1 Diabetes Immunotherapy.

靶向干细胞衍生的组织相关调节 T 细胞用于 1 型糖尿病免疫治疗。