Targeting of tumor cell DHHC3 to enhance anti-cancer immunity

靶向肿瘤细胞DHHC3增强抗癌免疫力

• 批准号: 9884868
• 负责人: MARTIN E HEMLER
• 金额: $ 40.02万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9884868
• 关键词: Ablation; Antioxidants; Breast Cancer Treatment; Cells; Enzymes; Failure; Goals; Growth; Human; Immune; In Vitro; Innate Immune System; Lead; Link; Malignant Neoplasms; Mammary Neoplasms; Mediating; Modeling; Mus; Mutate; Mutation; Natural Immunity; Natural Killer Cells; Nude Mice; Oxidative Regulation; Oxidative Stress; Phenotype; Physiology; Play; Prognostic Marker; Proteins; Regulation; Role; Sampling; Scheme; TXNIP gene; Testing; Transferase; Tumor Immunity; Up-Regulation; adaptive immunity; anti-cancer; experimental study; immune checkpoint blockade; in vivo; insight; knock-down; malignant breast neoplasm; neoplastic cell; novel; novel strategies; palmitoylation; premature; prevent; programmed cell death ligand 1; restoration; senescence; therapeutic target; tumor; tumor ablation; tumor growth; tumor xenograft

Project Summary Mobilization of both adaptive and innate immune cells has considerable utility in the treatment of breast cancer and other cancers. Here we provide a novel approach. Our central goal is to demonstrate how ablation of the protein acyl transferase, DHHC3, can enhance both adaptive and innate anti-cancer immunity. Towards achieving this goal, we have already shown that ZDHHC3 ablation i) markedly diminishes levels of checkpoint blockade molecule PD-L1 on tumor cells, and ii) disrupts CMTM6, a molecule needed to maintain PD-L1 expression, such that CMTM6 palmitoylation is abolished and subcellular localization markedly altered. Furthermore, iii) restoration with wild type DHHC3, but not enzymatically inactive DHHC3, restores PD-L1 levels. In addition, iv) ZDHHC3 ablation markedly reduces tumor xenograft growth in nude mice (but not in vitro) by a mechanism involving elevated oxidative stress, senescence, and tumor clearance by innate immune cells. Because the DHHC3 enzyme may regulate both adaptive and innate anti-cancer immunity, but is not needed for normal mouse physiology, it may be a useful therapeutic target. Our central guiding hypotheses are i) that DHHC3 ablation prevents CMTM6 palmitoylation, leading to degradation of unprotected PD- L1 on tumor cells, which enhances adaptive immunity and ii) that DHHC3 ablation also enhances innate immunity, with key regulators of oxidative stress (e.g. ERGIC3, TXNIP) and innate immune cells (e.g. NK cells) playing major roles. These hypotheses will be tested as follows: Aim 1, We will use a variety of in vitro and in vivo experiments to establish the extent to which DHHC3 ablation enhances adaptive immunity by a mechanism involving loss of CMTM6 palmitoylation leading to diminished PD-L1 expression. Aim 2, We will assess relative in vivo effects of mammary tumor cell DHHC3 ablation on innate and adaptive anti-breast cancer immunity, and we will evaluate key contributions of oxidative stress, senescence, and NK cells to innate immunity. Expected Impact: Results should support the utility of DHHC3 as a novel tumor target in breast cancer and other cancers, as DHHC3 ablation from tumor cells simultaneously enhances both adaptive and innate immunity, with CMTM6, PD-L1, oxidative stress, and NK cells playing key roles.

项目概要 适应性和先天免疫细胞的动员在乳腺癌的治疗中具有相当大的用途 和其他癌症。在这里，我们提供了一种新颖的方法。我们的中心目标是展示如何消融 蛋白质酰基转移酶 DHHC3 可以增强适应性和先天性抗癌免疫力。 为了实现这一目标，我们已经证明 ZDHHC3 消融 i) 显着降低了 肿瘤细胞上的检查点阻断分子 PD-L1，以及 ii) 破坏 CMTM6（一种维持肿瘤细胞正常功能所需的分子） PD-L1 表达，使得 CMTM6 棕榈酰化被废除，亚细胞定位显着改变。 此外，iii) 使用野生型 DHHC3 恢复，但不是酶促失活的 DHHC3，可以恢复 PD-L1 水平。此外，iv) ZDHHC3 消融显着降低了裸鼠中肿瘤异种移植物的生长（但在 体外）通过涉及先天免疫升高氧化应激、衰老和肿瘤清除的机制 细胞。因为 DHHC3 酶可以调节适应性和先天性抗癌免疫，但不能 正常小鼠生理学所需，它可能是一个有用的治疗靶点。我们的中心指导假设 i) DHHC3 消除可防止 CMTM6 棕榈酰化，导致未受保护的 PD- 的降解 肿瘤细胞上的 L1，增强适应性免疫，ii) DHHC3 消除也增强 先天免疫，具有氧化应激的关键调节因子（例如 ERGIC3、TXNIP）和先天免疫细胞 （例如 NK 细胞）发挥着重要作用。这些假设将按如下方式进行检验： 目标 1，我们将使用各种 体外和体内实验以确定 DHHC3 消融增强适应性的程度 通过涉及 CMTM6 棕榈酰化丧失导致 PD-L1 表达减少的机制来增强免疫力。 目标 2，我们将评估乳腺肿瘤细胞 DHHC3 消融对先天性和适应性的相对体内影响 抗乳腺癌免疫，我们将评估氧化应激、衰老和 NK 的关键贡献 细胞先天免疫。预期影响：结果应支持 DHHC3 作为新型肿瘤的实用性 乳腺癌和其他癌症的靶标，因为肿瘤细胞中 DHHC3 的消除同时增强了 适应性和先天免疫，其中 CMTM6、PD-L1、氧化应激和 NK 细胞发挥关键作用。