• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

APR-246 可提高肿瘤抗原性而不依赖于 p53。

APR-246 increases tumor antigenicity independent of p53.

机构信息

https://ror.org/02r109517 Department of Pharmacology, Swim Across America and Ludwig Collaborative Laboratory, Weill Cornell Medicine, New York, NY, USA.

https://ror.org/02r109517 Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.

出版信息

Life Sci Alliance. 2023 Oct 27;7(1). doi: 10.26508/lsa.202301999. Print 2024 Jan.

DOI:10.26508/lsa.202301999
PMID:37891002
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10610029/
Abstract

We previously reported that activation of p53 by APR-246 reprograms tumor-associated macrophages to overcome immune checkpoint blockade resistance. Here, we demonstrate that APR-246 and its active moiety, methylene quinuclidinone (MQ) can enhance the immunogenicity of tumor cells directly. MQ treatment of murine B16F10 melanoma cells promoted activation of melanoma-specific CD8 T cells and increased the efficacy of a tumor cell vaccine using MQ-treated cells even when the B16F10 cells lacked p53. We then designed a novel combination of APR-246 with the TLR-4 agonist, monophosphoryl lipid A, and a CD40 agonist to further enhance these immunogenic effects and demonstrated a significant antitumor response. We propose that the immunogenic effect of MQ can be linked to its thiol-reactive alkylating ability as we observed similar immunogenic effects with the broad-spectrum cysteine-reactive compound, iodoacetamide. Our results thus indicate that combination of APR-246 with immunomodulatory agents may elicit effective antitumor immune response irrespective of the tumor's p53 mutation status.

摘要

我们之前曾报道，APR-246 通过激活 p53 重编程肿瘤相关巨噬细胞，克服免疫检查点阻断耐药性。在这里，我们证明 APR-246 及其活性部分亚甲基喹诺酮（MQ）可以直接增强肿瘤细胞的免疫原性。MQ 处理小鼠 B16F10 黑色素瘤细胞促进了黑色素瘤特异性 CD8 T 细胞的激活，并增加了使用 MQ 处理细胞的肿瘤细胞疫苗的疗效，即使 B16F10 细胞缺乏 p53。然后，我们设计了 APR-246 与 TLR-4 激动剂单磷酰脂质 A 和 CD40 激动剂的新组合，以进一步增强这些免疫原性效应，并证明了显著的抗肿瘤反应。我们提出，MQ 的免疫原性效应与其巯基反应性烷化能力有关，因为我们观察到广谱半胱氨酸反应性化合物碘乙酰胺具有类似的免疫原性效应。因此，我们的研究结果表明，APR-246 与免疫调节剂的联合使用可能会引发有效的抗肿瘤免疫反应，而与肿瘤的 p53 突变状态无关。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d0/10610029/9d23ac7b4a19/LSA-2023-01999_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d0/10610029/6420207b3290/LSA-2023-01999_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d0/10610029/f809c038d0f6/LSA-2023-01999_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d0/10610029/dd3c3c9131ce/LSA-2023-01999_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d0/10610029/c7d2878af35c/LSA-2023-01999_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d0/10610029/81f356511ec0/LSA-2023-01999_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d0/10610029/83ebeb34f0af/LSA-2023-01999_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d0/10610029/69eebf2af35a/LSA-2023-01999_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d0/10610029/b499f10e91f3/LSA-2023-01999_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d0/10610029/1609f62467c9/LSA-2023-01999_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d0/10610029/9d23ac7b4a19/LSA-2023-01999_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d0/10610029/6420207b3290/LSA-2023-01999_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d0/10610029/f809c038d0f6/LSA-2023-01999_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d0/10610029/dd3c3c9131ce/LSA-2023-01999_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d0/10610029/c7d2878af35c/LSA-2023-01999_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d0/10610029/81f356511ec0/LSA-2023-01999_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d0/10610029/83ebeb34f0af/LSA-2023-01999_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d0/10610029/69eebf2af35a/LSA-2023-01999_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d0/10610029/b499f10e91f3/LSA-2023-01999_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d0/10610029/1609f62467c9/LSA-2023-01999_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d0/10610029/9d23ac7b4a19/LSA-2023-01999_FigS5.jpg

相似文献

1
APR-246 increases tumor antigenicity independent of p53.APR-246 可提高肿瘤抗原性而不依赖于 p53。
Life Sci Alliance. 2023 Oct 27;7(1). doi: 10.26508/lsa.202301999. Print 2024 Jan.
2
APR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells.APR-246克服卵巢癌细胞对顺铂和阿霉素的耐药性。
Cell Death Dis. 2015 Jun 18;6(6):e1794. doi: 10.1038/cddis.2015.143.
3
A thiol-bound drug reservoir enhances APR-246-induced mutant p53 tumor cell death.巯基结合药物库增强 APR-246 诱导的突变型 p53 肿瘤细胞死亡。
EMBO Mol Med. 2021 Feb 5;13(2):e10852. doi: 10.15252/emmm.201910852. Epub 2020 Dec 14.
4
Increased p53 expression induced by APR-246 reprograms tumor-associated macrophages to augment immune checkpoint blockade.APR-246 通过诱导 p53 表达重塑肿瘤相关巨噬细胞，增强免疫检查点阻断作用。
J Clin Invest. 2022 Sep 15;132(18):e148141. doi: 10.1172/JCI148141.
5
APR-246 reactivates mutant p53 by targeting cysteines 124 and 277.APR-246 通过靶向半胱氨酸 124 和 277 重新激活突变型 p53。
Cell Death Dis. 2018 May 1;9(5):439. doi: 10.1038/s41419-018-0463-7.
6
In situ immunogenic clearance induced by a combination of photodynamic therapy and rho-kinase inhibition sensitizes immune checkpoint blockade response to elicit systemic antitumor immunity against intraocular melanoma and its metastasis.光动力疗法联合 rho 激酶抑制诱导的原位免疫清除增强免疫检查点阻断反应，引发针对眼内黑色素瘤及其转移的系统性抗肿瘤免疫。
J Immunother Cancer. 2021 Jan;9(1). doi: 10.1136/jitc-2020-001481.
7
Intratumoral immunotherapy using a TLR2/3 agonist, L-pampo, induces robust antitumor immune responses and enhances immune checkpoint blockade.使用 TLR2/3 激动剂 L-pampo 进行肿瘤内免疫治疗可诱导强烈的抗肿瘤免疫反应，并增强免疫检查点阻断。
J Immunother Cancer. 2022 Jun;10(6). doi: 10.1136/jitc-2022-004799.
8
Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ).小分子甲撑喹啉酮（MQ）激活致癌 p53 突变体的结构基础。
Nat Commun. 2021 Dec 3;12(1):7057. doi: 10.1038/s41467-021-27142-6.
9
B Cells Are Required to Generate Optimal Anti-Melanoma Immunity in Response to Checkpoint Blockade.B 细胞对于针对检查点阻断的黑色素瘤免疫反应的产生是必需的。
Front Immunol. 2022 May 26;13:794684. doi: 10.3389/fimmu.2022.794684. eCollection 2022.
10
Boiling histotripsy and in-situ CD40 stimulation improve the checkpoint blockade therapy of poorly immunogenic tumors.煮沸声动力疗法联合原位 CD40 刺激增强免疫原性差肿瘤的免疫检查点阻断治疗。
Theranostics. 2021 Jan 1;11(2):540-554. doi: 10.7150/thno.49517. eCollection 2021.

引用本文的文献

1
Neuroblastoma response to RAS-MAPK inhibitors and APR-246 (eprenetapopt) co-treatment is dependent on SLC7A11.神经母细胞瘤对RAS-MAPK抑制剂和APR-246（依普萘妥凋亡素）联合治疗的反应取决于溶质载体家族7成员11（SLC7A11）。
Front Oncol. 2024 Dec 6;14:1433256. doi: 10.3389/fonc.2024.1433256. eCollection 2024.
2
Unraveling the Guardian: p53's Multifaceted Role in the DNA Damage Response and Tumor Treatment Strategies.解读守护者：p53在DNA损伤应答及肿瘤治疗策略中的多面角色
Int J Mol Sci. 2024 Dec 1;25(23):12928. doi: 10.3390/ijms252312928.

本文引用的文献

1
Increased p53 expression induced by APR-246 reprograms tumor-associated macrophages to augment immune checkpoint blockade.APR-246 通过诱导 p53 表达重塑肿瘤相关巨噬细胞，增强免疫检查点阻断作用。
J Clin Invest. 2022 Sep 15;132(18):e148141. doi: 10.1172/JCI148141.
2
Phase Ib study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with advanced or metastatic solid tumors.eprenetapopt（APR-246）联合 pembrolizumab 治疗晚期或转移性实体瘤的 Ib 期研究。
ESMO Open. 2022 Oct;7(5):100573. doi: 10.1016/j.esmoop.2022.100573. Epub 2022 Sep 7.
3
B cells and tertiary lymphoid structures as determinants of tumour immune contexture and clinical outcome.
B 细胞和三级淋巴结构作为肿瘤免疫微环境和临床结局的决定因素。
Nat Rev Clin Oncol. 2022 Jul;19(7):441-457. doi: 10.1038/s41571-022-00619-z. Epub 2022 Apr 1.
4
Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer.仑伐替尼联合帕博利珠单抗治疗晚期子宫内膜癌。
N Engl J Med. 2022 Feb 3;386(5):437-448. doi: 10.1056/NEJMoa2108330. Epub 2022 Jan 19.
5
Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ).小分子甲撑喹啉酮（MQ）激活致癌 p53 突变体的结构基础。
Nat Commun. 2021 Dec 3;12(1):7057. doi: 10.1038/s41467-021-27142-6.
6
Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer.派姆单抗治疗持续性、复发性或转移性宫颈癌。
N Engl J Med. 2021 Nov 11;385(20):1856-1867. doi: 10.1056/NEJMoa2112435. Epub 2021 Sep 18.
7
High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types.高肿瘤突变负担未能预测所有癌症类型的免疫检查点阻断反应。
Ann Oncol. 2021 May;32(5):661-672. doi: 10.1016/j.annonc.2021.02.006. Epub 2021 Mar 15.
8
Pembrolizumab versus brentuximab vedotin in relapsed or refractory classical Hodgkin lymphoma (KEYNOTE-204): an interim analysis of a multicentre, randomised, open-label, phase 3 study.帕博利珠单抗对比本妥昔单抗维布妥昔单抗治疗复发或难治性经典型霍奇金淋巴瘤（KEYNOTE-204）：一项多中心、随机、开放标签、3 期研究的中期分析。
Lancet Oncol. 2021 Apr;22(4):512-524. doi: 10.1016/S1470-2045(21)00005-X. Epub 2021 Mar 12.
9
Transketolase regulates sensitivity to APR-246 in p53-null cells independently of oxidative stress modulation.转酮醇酶通过独立于氧化应激调节的方式调节 p53 缺失细胞对 APR-246 的敏感性。
Sci Rep. 2021 Feb 24;11(1):4480. doi: 10.1038/s41598-021-83979-3.
10
Oncolytic virotherapy-mediated anti-tumor response: a single-cell perspective.溶瘤病毒治疗介导的抗肿瘤反应：单细胞视角。
Cancer Cell. 2021 Mar 8;39(3):394-406.e4. doi: 10.1016/j.ccell.2020.12.022. Epub 2021 Jan 21.