Nucleus Accumbens-Associated Protein-1 in Melanoma Immunotherapy

项目概要/摘要 由于黑色素瘤主要表达肿瘤特异性新抗原（Ags），因此免疫治疗如过继细胞免疫治疗（Adoptive cell 基于转移的疗法（ACT）被认为是对这种臭名昭著的致命疾病的有希望的治疗选择。 然而，由于各种可能削弱治疗免疫力的因素， 这种补救办法的效果仍然不太令人满意。重要的是，越来越多的证据表明， 免疫细胞和肿瘤细胞的代谢对ACT的效力有显著影响， 重编程可能是加强免疫治疗的可行靶点。核相关 蛋白-1（NAC 1）是属于BTB/POZ基因家族的转录辅助调节因子，并且在BTB/POZ基因中高度表达。 包括黑色素瘤在内的几种癌症。包括我们自己在内的已发表研究表明，NAC 1 不仅赋予致癌潜力，而且通过其转录破坏治疗结果， 独立或非独立函数。最近，我们发现NAC 1可以通过以下途径促进糖酵解： 它与HIF-1a的相互作用，是T细胞发育、存活和功能所必需的， 肿瘤细胞我们还发现，NAC 1对主要组织相容性的肿瘤表达有负面影响， NAC 1基因表达的改变发生在多能造血干细胞的分化过程中。 干细胞（PSC）来源的T细胞，这种改变伴随着一些表达的变化， 其他基因。基于这些有趣的发现，我们假设NAC 1介导的代谢 重编程抑制抗肿瘤免疫;靶向NAC 1将加速死亡或降低抗肿瘤免疫的恢复力。 肿瘤和抑制性免疫细胞，并调节肿瘤Ags，检查点分子的表达 和相关蛋白质，从而缓解免疫抑制并增强ACT对 黑素瘤为了检验这些假设，当前的多PI应用程序提出了以下高度 互动的具体目标：（1）确定NAC 1在T细胞中的新作用;（2）确定NAC 1在T细胞中的作用。 肿瘤NAC 1在黑色素瘤免疫逃逸中的作用;（3）确定靶向NAC 1对ACT的影响 对抗黑素瘤这个多PI项目结合了杨实验室在癌症生物学方面的优势， 宋实验室在肿瘤免疫学方面的专长。我们已经建立了小鼠和人类的PSC- 衍生的抗原特异性CD 8 + T淋巴细胞，以及鼠同基因和人源化（NOD-scid IL 2 rgnull） 小鼠黑色素瘤模型的建议的研究，并准备好实现上述目标。 该项目的完成不仅将揭示NAC 1作为肿瘤特异性的独特分子决定因素， 免疫反应，并揭示了NAC 1在癌症病理学中的重要性，但也提供了 通过NAC 1靶向策略增强ACT抗黑色素瘤的新治疗机会。

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.