Nucleus Accumbens-Associated Protein-1 in Melanoma Immunotherapy

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)，过继细胞等免疫治疗 基于转移的治疗(ACT)被认为是这种臭名昭著的致命疾病的一种有前途的治疗选择。 然而，由于各种可能削弱治疗免疫力的因素，临床疗效和益处 这一补救措施的效果仍然不太令人满意。重要的是，越来越多的证据表明新陈代谢状态 免疫细胞和肿瘤细胞的数量对ACT的效力和代谢都有重大影响 重新编程可能是加强免疫治疗的一个可行的目标。伏隔相关核 蛋白-1(Protein-1，NAC1)是BTB/POZ基因家族中的一种转录辅助调节因子，高表达 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的研究表明，NAC1 不仅赋予致癌潜力，而且还通过其转录破坏治疗结果- 相关函数或非独立函数。最近，我们发现NAC1可以通过 它与HIF-1a相互作用，对T细胞的发育、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有负面影响 复合体(MHC)；NAC1基因表达的变化发生在多能性细胞分化过程中 干细胞(PSC)来源的T细胞，这种变化伴随着许多基因表达的变化 其他基因的基因。基于这些有趣的发现，我们假设NAC1介导的代谢 重编程抑制抗肿瘤免疫；靶向NAC1会加速死亡或降低弹性 肿瘤和抑制性免疫细胞并调节肿瘤AGS、检查点分子的表达 及相关蛋白，从而解除免疫抑制，增强ACT抗肿瘤作用 黑色素瘤。为了验证这些假设，当前的多重PI应用程序提出了以下高度建议 交互作用的特定目标：(1)确定NAC1在T细胞中的新角色；(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；(3)确定靶向NAC1在ACT中的作用 对抗黑色素瘤。这个多PI项目结合了杨实验室在癌症生物学方面的优势和 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的PSC- 衍生抗原特异性CD8 T淋巴细胞及其同源和人源化(NOD-SCID IL2rgnull) 为拟议的研究建立小鼠黑色素瘤模型，并已做好准备实现上述目标。 该项目的完成不仅将发现NAC1作为肿瘤特异性的独特分子决定因素 免疫反应，并阐明了NAC1在癌症病理生物学中的重要性，但也提供了 通过NAC1靶向策略增强抗黑色素瘤ACT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.