ALDH Inhibition as Modulator of Tumor Immunobiology

尽管对标准护理方案进行了微小的改进，但卵巢癌患者的总体存活率 (OvCa)几十年来没有明显变化。有一种明显的未得到满足的临床需求，即开发新的 这种高度侵袭性疾病的治疗在女性癌症死亡中排名第五，死亡率排名第三 与所有癌症的发病率之比。乙醛脱氢酶-1A酶(ALDH1A)是一种治疗靶点 对Ovca来说。ALDH1A酶在卵巢癌启动细胞中上调，在那里它们介导 维甲酸(RA)的生物合成，调节多种细胞过程。我们最近证明了 抑制ALDH1a(ALDHi)具有双重作用：它可以直接靶向肿瘤细胞减缓增殖和 作用于免疫细胞，增强树突状细胞(DC)和CD8+T细胞的增殖反应。我们的 最重要的假设是ALDHi可以作为免疫调节剂(通过单个RA受体 RAR/RXR和NR4A1共同受体)，可用于加强卵巢癌的免疫治疗方法。 为了验证这一假设，我们的五年期项目R01CA238315，这项研究补充资料的父母拨款 促进健康相关研究的多样性，提出三个具体目标(SA)SA1：识别RA ALDHi诱导肿瘤细胞坏死的受体及其下游因子 ALDHi诱导的CIC坏死性下垂为炎性细胞死亡。SA2：评估ALDHi对主机DC和T的影响 细胞。SA3：检测ALDHi对OvCa免疫治疗的促进作用。目前为期一年的项目 我们的新发现表明，除了它们在DC和CD8 T细胞中的免疫促进功能外， ALDHi还可以降低肿瘤相关巨噬细胞()的出现频率，这是一种至关重要的免疫细胞 具有免疫抑制、促肿瘤作用的亚群。目前为期一年的提案的目标是 将我们的研究(最初集中在DC和T细胞)扩展到(1)确定ALDHi诱导效应的机制 关于和(2)阐明这些ALDHi效应在调节肿瘤中的下游后果 微环境和增强免疫治疗反应。为了实现这一点，我们将使用原代巨噬细胞 体外来源于血液(人)或骨髓前体细胞(小鼠)，在M1/M2诱导下成熟 在ALDHi存在或不存在的情况下。NR4A1受累将用骨髓进行解剖 来自NR4A1报告小鼠的前体和靶标特异性将在NR4A1缺失小鼠中得到确认。免疫者 在卵巢原位攻击NR4A1小鼠中，的调节作用将在体内进一步剖析 肿瘤，用ALDHi或赋形剂对照治疗。 影响：该项目符合美国国立卫生研究院的使命，即促进从事以下研究的研究人员的多样性 与健康相关的科学。这里提出的研究将确定ALDHi在卵巢癌免疫治疗中的新角色。 鉴于ALDH与癌症的治疗耐药性广泛相关，我们的工作将具有深远的影响 用于癌症治疗。

Despite small improvements to standard of care protocols, the overall survival of patients with ovarian cancer (OvCa) has not significantly changed for several decades. There is a clear unmet clinical need to develop new therapies for this highly aggressive disease ranking 5th in cancer deaths in women, with the 3rd highest mortality to incidence ratio of all cancers. Aldehyde dehydrogenase-1A enzymes (ALDH1A) represent a therapeutic target for OvCa. ALDH1A enzymes are upregulated in ovarian cancer initiating cells where they mediate the biosynthesis of retinoic acid (RA), to regulate numerous cellular processes. We recently demonstrated that inhibition of ALDH1A (ALDHi) can have a dual effect: it can directly target tumor cells to slow proliferation and act on immune cells to enhance proliferative response of both dendritic cells (DC) and CD8+ T cells. Our overarching hypothesis is that ALDHi can act as an immune modulator (via individual RA receptors RAR/RXR and NR4A1 co-receptor) and can be used to enhance immunotherapeutic approaches in OvCa. To test this hypothesis, our five-year project R01CA238315, the parent grant to this Research Supplement to Promote Diversity in Health-Related Research, proposes three specific aims (SA) SA1: To identify the RA receptors and downstream factors that drive ALDHi induced necrosis in tumor cells and to determine whether ALDHi-induced CIC necroptosis is inflammatory cell death. SA2: Assess the impact of ALDHi on host DC and T cells. SA3: To determine the ability of ALDHi to enhance immunotherapy in OvCa. The current, one-year project builds on our new findings showing that, in addition to their immune promoting function in DCs and CD8 T cells, ALDHi also lower the frequency of tumor associated macrophages (TAM), a critically important immune cell subset with immune suppressive, tumor-promoting function. The goal of the current one-year proposal is to extend our studies (originally focused on DC and T cells) to (1) identify the mechanisms of ALDHi induced effects on TAM and (2) elucidate the downstream consequences of these ALDHi effects on modulating the tumor microenvironment and enhancing immune therapy response. To achieve this, we will use primary macrophages derived ex vivo from blood (human) or bone marrow precursors (mice) and matured under M1/M2 inducing conditions in the presence or absence of ALDHi. NR4A1 involvement will be dissected using bone marrow precursors from NR4A1 reporter mice and target specificity will be confirmed in NR4A1 null mice. The immune modulatory roles of TAM will be further dissected in vivo, in NR4A1 mice challenged orthotopically with ovarian tumors and treated with ALDHi or vehicle control. IMPACT: This project is in line with the NIH mission to promote diversity among investigators doing research in health-related sciences. The studies proposed here will define new roles for a ALDHi in immunotherapy in OvCa. Given ALDH is broadly linked with therapeutic resistance in cancer, our work will have far-reaching implications for cancer therapy.