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

• 批准号: 10064606
• 负责人: Jianxun Jim Song
• 金额: $ 56.19万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-03 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064606
• 关键词: Adoptive Cell Transfers; Affect; Antigens; Apoptosis; Autophagocytosis; Biological Models; CD8-Positive T-Lymphocytes; CTLA4 gene; Cancer Biology; Cells; Cessation of life; Clinical; Cytotoxic T-Lymphocytes; Development; Disease; Eragrostis; FASN gene; Fibrinogen; Gene Expression; Gene Family; Genes; Genetic Transcription; Glycolysis; Goals; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunology; Immunosuppression; Immunosuppressive Agents; Immunotherapy; In Vitro; Laboratories; Light; 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; Physiological; Play; Pluripotent Stem Cells; Proteins; Publishing; 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 Suppressor Proteins; Tumor-associated macrophages; Tumor-infiltrating immune cells; Yang; base; 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

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.

项目摘要/摘要 由于黑色素瘤主要表达肿瘤特异性新抗原（AGS），因此免疫疗法（例如适应性细胞） 基于转移的治疗（ACT）被认为是这种臭名昭著的致命疾病的承诺治疗选择。 然而，由于各种因素可能会削弱治疗免疫力，临床结果和益处 记住这一点仍然不太满意。重要的是，积累证据表明代谢状态 免疫细胞和肿瘤细胞都对ACT的效力都有重大影响，并且代谢 重编程可能代表了加强免疫疗法的可行靶标。伏隔核相关 蛋白-1（NAC1）是属于BTB/POZ基因家族的转录共同调节剂，高度表达 在包括黑色素瘤在内的几种类型的癌症中。包括我们自己在内的已发表的研究表明NAC1 不仅赋予致癌潜力，而且还通过其转录来破坏治疗结果 依赖或无关的函数。最近，我们发现NAC1可以通过 它与HIF-1A的相互作用，并且至关重要的是T细胞的发展，生存和功能以及 肿瘤细胞。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 复合物（MHC）; NaC1基因表达的改变发生在多能的分化过程中 干细胞（PSC）衍生的T细胞，这种改变是通过数字表达式的变化来实现的 其他基因。基于这些有趣的发现，我们假设NAC1介导的代谢 重编程可抑制抗肿瘤免疫力；靶向NAC1将死亡或降低 肿瘤和抑制免疫细胞，并调节肿瘤AG的表达，检查点分子 以及相关的蛋白质，从而缓解免疫抑制并增强行动效率 黑色素瘤。为了检验这些假设，当前的多个PI应用程序提出以下建议 交互式特定目的：（1）确定NaC1在T细胞中的新作用； （2）确定 黑色素瘤免疫逃生中的肿瘤NaC1； （3）确定靶向NAC1在ACT中的影响 反对黑色素瘤。这个多重PI项目将杨实验室在癌症生物学方面的力量与 歌曲实验室在肿瘤免疫学方面的专业知识。我们已经建立了老鼠和人类PSC- 衍生的抗原特异性CD8+ T淋巴细胞，以及鼠的合成和人源化（点数scid IL2RGNULL） 小鼠黑色素瘤模型用于拟议的研究，并且有毒化的毒品可实现上述目的。 该项目的完成不仅会发现NAC1作为确定肿瘤特异性的独特分子 免疫反应，并为NAC1在癌症病理学中的重要性提供了新的启示，但也提供 通过以NAC1为目标的策略，新的热机会来增强针对黑色素瘤的作用。