Fate control engagement augments NK cell responses in LV/hu-IL-12 transduced sarcoma

IF 2.8 4区 医学 Q2 PATHOLOGY Experimental and molecular pathology Pub Date : 2024-05-09 DOI:10.1016/j.yexmp.2024.104898
Mary Jo Rademacher , Mary L. Faber , Kathleen M. Bone , Jeffrey A. Medin , Nathan J. Schloemer
{"title":"Fate control engagement augments NK cell responses in LV/hu-IL-12 transduced sarcoma","authors":"Mary Jo Rademacher ,&nbsp;Mary L. Faber ,&nbsp;Kathleen M. Bone ,&nbsp;Jeffrey A. Medin ,&nbsp;Nathan J. Schloemer","doi":"10.1016/j.yexmp.2024.104898","DOIUrl":null,"url":null,"abstract":"<div><h3>Introduction</h3><p>NK cells are an untapped resource for cancer therapy. Sarcomas transduced with lentiviruses to express human IL-12 are only cleared in mice bearing mature human NK cells. However, systemic inflammation limits IL-12 utilization. Fate control a.k.a. “suicide mechanisms” regulate unchecked systemic inflammation caused by cellular immunotherapies. Despite increasing utilization, there remains limited data on immune consequences or tumor-directed effects of fate control.</p></div><div><h3>Objectives</h3><p>We sought to engage the mutant thymidylate kinase (mTMPK) metabolic fate control system to regulate systemic inflammation and assess the impact on NK cell effector functions.</p></div><div><h3>Methods</h3><p>Primary human sarcoma short-passage samples and cell lines were transduced with LV/hu-IL-12_mTMPK engineering expression of IL-12 and an AZT-associated fate control enzyme. We assessed transduced sarcoma responses to AZT engagement and subsequent modulation of NK cell functions as measured by inflammatory cytokine production and cytotoxicity.</p></div><div><h3>Results</h3><p>AZT administration to transduced (LV/hu-IL-12_mTMPK) short-passage primary human sarcomas and human Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma cell lines, abrogated the robust expression of human IL-12. Fate control activation elicited a specific dose-dependent cytotoxic effect measured by metabolic activity (WST-1) and cell death (Incucyte). NK effector functions of IFN-γ and cytotoxic granule release were significantly augmented despite IL-12 abrogation. This correlated with preferentially induced expression of NK cell activation ligands.</p></div><div><h3>Conclusions</h3><p>mTMPK fate control engagement terminates transduced sarcoma IL-12 production and triggers cell death, but also augments an NK cell-mediated response coinciding with metabolic stress activating surface ligand induction. Fate control engagement could offer a novel immune activation method for NK cell-mediated cancer clearance.</p></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"137 ","pages":"Article 104898"},"PeriodicalIF":2.8000,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0014480024000170/pdfft?md5=5c6bcb3072ad12079605419d64782842&pid=1-s2.0-S0014480024000170-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental and molecular pathology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0014480024000170","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PATHOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Introduction

NK cells are an untapped resource for cancer therapy. Sarcomas transduced with lentiviruses to express human IL-12 are only cleared in mice bearing mature human NK cells. However, systemic inflammation limits IL-12 utilization. Fate control a.k.a. “suicide mechanisms” regulate unchecked systemic inflammation caused by cellular immunotherapies. Despite increasing utilization, there remains limited data on immune consequences or tumor-directed effects of fate control.

Objectives

We sought to engage the mutant thymidylate kinase (mTMPK) metabolic fate control system to regulate systemic inflammation and assess the impact on NK cell effector functions.

Methods

Primary human sarcoma short-passage samples and cell lines were transduced with LV/hu-IL-12_mTMPK engineering expression of IL-12 and an AZT-associated fate control enzyme. We assessed transduced sarcoma responses to AZT engagement and subsequent modulation of NK cell functions as measured by inflammatory cytokine production and cytotoxicity.

Results

AZT administration to transduced (LV/hu-IL-12_mTMPK) short-passage primary human sarcomas and human Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma cell lines, abrogated the robust expression of human IL-12. Fate control activation elicited a specific dose-dependent cytotoxic effect measured by metabolic activity (WST-1) and cell death (Incucyte). NK effector functions of IFN-γ and cytotoxic granule release were significantly augmented despite IL-12 abrogation. This correlated with preferentially induced expression of NK cell activation ligands.

Conclusions

mTMPK fate control engagement terminates transduced sarcoma IL-12 production and triggers cell death, but also augments an NK cell-mediated response coinciding with metabolic stress activating surface ligand induction. Fate control engagement could offer a novel immune activation method for NK cell-mediated cancer clearance.

Abstract Image

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
命运控制参与增强了 LV/hu-IL-12 转导肉瘤中的 NK 细胞反应
导言NK细胞是一种尚未开发的癌症治疗资源。用慢病毒转导表达人类 IL-12 的肉瘤只有在携带成熟人类 NK 细胞的小鼠体内才能被清除。然而,全身性炎症限制了IL-12的利用。命运控制又称 "自杀机制",可调节细胞免疫疗法引起的不受限制的全身炎症。我们试图利用突变胸苷酸激酶(mTMPK)代谢命运控制系统来调节全身炎症,并评估其对 NK 细胞效应功能的影响。方法用 LV/hu-IL-12_mTMPK 工程表达 IL-12 和 AZT 相关命运控制酶转导原发性人类肉瘤短通道样本和细胞系。结果对转导(LV/hu-IL-12_mTMPK)的短通道原代人类肉瘤和人类尤文肉瘤、骨肉瘤和横纹肌肉瘤细胞系施用 AZT 后,人类 IL-12 的强健表达消失了。通过代谢活性(WST-1)和细胞死亡(Incucyte)测量,命运控制激活可引起特定剂量依赖性的细胞毒性效应。尽管 IL-12 被削弱,但 IFN-γ 和细胞毒性颗粒释放的 NK 效应功能仍显著增强。结论mTMPK命运控制参与能终止转导肉瘤IL-12的产生并引发细胞死亡,还能增强NK细胞介导的反应,同时还能激活表面配体诱导的代谢应激。命运控制参与可为 NK 细胞介导的癌症清除提供一种新的免疫激活方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
CiteScore
8.90
自引率
0.00%
发文量
78
审稿时长
11.5 weeks
期刊介绍: Under new editorial leadership, Experimental and Molecular Pathology presents original articles on disease processes in relation to structural and biochemical alterations in mammalian tissues and fluids and on the application of newer techniques of molecular biology to problems of pathology in humans and other animals. The journal also publishes selected interpretive synthesis reviews by bench level investigators working at the "cutting edge" of contemporary research in pathology. In addition, special thematic issues present original research reports that unravel some of Nature''s most jealously guarded secrets on the pathologic basis of disease. Research Areas include: Stem cells; Neoangiogenesis; Molecular diagnostics; Polymerase chain reaction; In situ hybridization; DNA sequencing; Cell receptors; Carcinogenesis; Pathobiology of neoplasia; Complex infectious diseases; Transplantation; Cytokines; Flow cytomeric analysis; Inflammation; Cellular injury; Immunology and hypersensitivity; Athersclerosis.
期刊最新文献
Corrigendum to "Irisin and neuroinflammation: Challenges and opportunities" [Experimental and Molecular Pathology 140 (2024) 104941]. Diagnostic criteria and therapeutic implications of rapid-onset demyelinating polyneuropathies Irisin and neuroinflammation: Challenges and opportunities Assessing pathogenicity of mismatch repair variants of uncertain significance by molecular tumor analysis Impaired immunoproteasomal function exacerbates renal ischemia-reperfusion injury
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1