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: 10357889
• 负责人: MARTIN E HEMLER
• 金额: $ 39.22万
• 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/10357889
• 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; 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; prognostic indicator; 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.

项目摘要 动员适应性免疫细胞和先天免疫细胞在乳腺癌的治疗中有相当大的作用。 和其他癌症。在这里，我们提供了一种新的方法。我们的中心目标是演示如何消融 蛋白质酰基转移酶DHHC3可以增强获得性和先天抗癌免疫。 为了实现这一目标，我们已经表明，ZDHHC3消融I)显著降低了 检查点阻断分子PD-L1在肿瘤细胞上，以及ii)破坏CMTM6，一个需要维持的分子 PD-L1的表达，如CMTM6棕榈酰化被取消，亚细胞定位明显改变。 此外，iii)用野生型DHHC3恢复，而不是酶失活的DHHC3，恢复PD-L1 级别。此外，IV)消融ZDHHC3显著减少了裸鼠移植瘤的生长(但不是在 体外)通过先天免疫提高氧化应激、衰老和肿瘤清除的机制 细胞。因为DHHC3酶可能调节获得性和先天抗癌免疫，但不是 这是正常小鼠生理所需的，可能是一个有用的治疗靶点。我们的中心指导性假设 是i)DHHC3消融阻止CMTM6棕榈酰化，导致无保护的PD- L1，可增强获得性免疫；ii)DHHC3消融也可增强 先天免疫，氧化应激的关键调节者(如ERGIC3，TXNIP)和先天免疫细胞 (如NK细胞)起主要作用。这些假设将被检验如下：目标1，我们将使用各种 体外和体内实验确定DHHC3消融在多大程度上增强适应性 免疫机制包括CMTM6棕榈酰化缺失导致PD-L1表达减少。 目的2，我们将评估乳腺肿瘤细胞DHHC3在体内对先天性和适应性的相对影响 抗乳腺癌免疫，我们将评估氧化应激、衰老和NK的关键作用 细胞的先天免疫力。预期影响：结果应该支持DHHC3作为一种新的肿瘤的实用性 乳腺癌和其他癌症的靶点，因为从肿瘤细胞中去除DHHC3同时增强了这两种肿瘤 获得性免疫和先天免疫，其中CMTM6、PD-L1、氧化应激和NK细胞起关键作用。