Project III: Engineering immunogenic cell death in melanoma and renal cell carcinoma.
项目 III:工程化黑色素瘤和肾细胞癌中的免疫原性细胞死亡。
基本信息
- 批准号:10705788
- 负责人:
- 金额:$ 49.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-16 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:APAF1 geneAbscopal effectAffectAllograftingAntigensApoptosisBAX geneBCL1 OncogeneCASP9 geneCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCaspaseCell DeathCell LineCell Membrane PermeabilityCell NucleusCellsClear cell renal cell carcinomaComputer ModelsCytosolDimensionsDistantEcosystemEngineeringEpigenetic ProcessEvolutionGene ExpressionGenetic EngineeringGenetically Engineered MouseGoalsHumanImmuneImmune responseImmune systemImmunofluorescence ImmunologicImmunologic MemoryImmunologicsImmunotherapyIn complete remissionInflammatoryInner mitochondrial membraneInterferon Type ILabelLeadLuciferasesMelanoma CellMemorial Sloan-Kettering Cancer CenterMitochondriaMitochondrial DNAModelingMolecularMusMutationNecrosisNeoplasm MetastasisOuter Mitochondrial MembranePathway interactionsPatientsProbabilityProcessProtein FamilyRNARecurrent tumorRenal Cell CarcinomaResearch PersonnelResolutionSamplingStimulator of Interferon GenesSystemSystems BiologyT cell receptor repertoire sequencingT-LymphocyteT-cell receptor repertoireThe Cancer Genome AtlasTherapeuticTransplantationTumor Immunityadaptive immune responseanti-CTLA-4 therapyanti-PD-1cancer carecancer cellcancer typecell typecytochrome cdraining lymph nodeimmune checkpoint blockadeimmunogenicimmunogenic cell deathimmunogenicityimprovedin vivoinsightmelanomamouse modelmultiple omicsnovelprogramsresponsesuccesssurvival outcometumortumor heterogeneitytumor progression
项目摘要
Project III. Engineering immunogenic cell death in melanoma and renal cell carcinoma
Experimental Lead: Cheng
Computational Lead: Leslie
Experimental Co-Investigator: Li
PROJECT SUMMARY
Recent approval of immune checkpoint blockade (ICB) in multiple cancer types has revolutionized cancer care,
but only a small fraction of patients achieve a durable complete response. Hence, there is an urgent need for
novel immunotherapy-based therapeutic strategies to enhance response and offer long-term survival benefits.
We hypothesize that induction of immunogenic cancer cell death is one of such strategy. Necroptosis and
pyroptosis, two forms of programmed necrosis, are pro-inflammatory and probably immunogenic. By contrast,
mitochondrial apoptosis is generally considered immunologically silent. The BCL-2 family proteins are central
regulators of mitochondrial apoptosis. BAX and BAK, once activated by BH3-only molecules, trigger
mitochondrial outer membrane permeabilization (MOMP), which releases cytochrome c to activate the
apoptosome and caspases. Recent paradigm-shifting discoveries have shown that BAX/BAK activation in the
absence of caspases can trigger the release of mitochondrial DNA to the cytosol through a process called
“mitochondrial inner membrane permeabilization” (MIMP), which activates the cGAS/STING pathway and type I
interferon response. These findings indicate that this form of BAX/BAK-dependent, caspase-independent cell
death, which we termed “mimptosis”, is highly inflammatory. Here, we engineer models of inducible cell death in
murine melanoma and genetically engineered mouse models (GEMMs) of clear cell renal cell carcinoma
(ccRCC) to compare the immune response to apoptosis, mimptosis, pyroptosis, and necroptosis in vivo. Our
goal is to identify the most immunogenic cell death that not only kills cancer cells but also instructs the immune
system to enhance ICB response and elucidate the underlying molecular mechanisms using a comprehensive
systems biology approach. In Aim 1, we will characterize the impact of different kinds of engineered
immunogenic cell death (ICD) on tumor-immune ecosystem dynamics melanoma using integrated single-cell
multiome, paired single-cell RNA and T cell receptor (TCR) sequencing, and multiplexed immunofluorescence.
Computational modeling will define immune cell gene expression and regulatory programs in response to ICD
to inform therapeutic strategies to improve ICB. In Aim 2, we will determine whether and how immunogenic cell
abrogates tumor progression and metastasis and generates immunological memory against tumor rechallenge
in GEMMs of ccRCC. A comprehensive multidimensional assessment and computational modeling of tumor-
immune ecosystem evolution, T cell epigenetic and functional states, and TCR repertoire in response to different
types of cell death will unravel mechanisms that promote anti-tumor immunity. TCGA analysis revealed that low
expression of apoptosome components, APAF1 and Caspase-9, is associated with better survival outcomes,
suggesting that caspase-independent mimptosis may activate anti-tumor immunity and confer survival benefits
in ccRCC. We will assess this hypothesis by performing single-nucleus multiome and MxIF in patient ccRCC
samples to characterize tumor-immune cross-talk comparing ccRCC with low vs high apoptosome expression.
项目III黑色素瘤和肾癌的工程化免疫原性细胞死亡
实验领队:程
计算主管:莱斯利
实验联合调查员:李
项目总结
最近批准免疫检查点阻断(ICB)治疗多种癌症类型,使癌症治疗发生了革命性的变化,
但只有一小部分患者获得了持久的完全缓解。因此,迫切需要
以免疫治疗为基础的新治疗策略,以增强反应并提供长期生存益处。
我们假设诱导免疫原性癌细胞死亡是其中一种策略。坏死性下垂和
上睑下垂是程序性坏死的两种形式,是促炎的,可能是免疫原性的。相反,
线粒体凋亡通常被认为是免疫沉默的。BCL-2家族蛋白是核心蛋白
线粒体凋亡的调节者。BAX和BAK一旦被仅BH3分子激活,就会触发
线粒体外膜通透性(MOMP),释放细胞色素c激活
凋亡体和半胱氨酸天冬氨酸酶。最近的范式转换发现表明BAX/BAK在脑内的激活
半胱氨酸氨基转移酶的缺失可以触发线粒体DNA释放到细胞质中,这个过程被称为
“线粒体内膜通透性”(MIMP),激活cGAS/STING途径和I型
干扰素反应。这些发现表明,这种形式的Bax/BAK依赖于caspase的细胞
死亡,我们称之为“小儿麻痹症”,具有高度的煽动性。在这里,我们设计了诱导细胞死亡的模型
小鼠黑色素瘤和基因工程小鼠肾透明细胞癌模型
(CcRCC)比较体内对细胞凋亡、小儿麻痹、下垂和坏死性下垂的免疫反应。我们的
目标是识别免疫原性最强的细胞死亡,这种细胞死亡不仅能杀死癌细胞,还能指导免疫
系统,以增强ICB反应和阐明潜在的分子机制使用全面
系统生物学方法。在目标1中,我们将描述不同类型的工程技术的影响
免疫原性细胞死亡(ICD)对黑色素瘤肿瘤免疫生态系统动力学的影响
多组、配对单细胞RNA和T细胞受体(TCR)测序以及多重免疫荧光。
计算模型将定义免疫细胞基因表达和应对ICD的调节程序
为改善ICB的治疗策略提供信息。在目标2中,我们将确定免疫原细胞是否以及如何
阻断肿瘤的进展和转移,并产生免疫记忆以抵御肿瘤的再攻击
在CCRCC的GEMMS中。肿瘤的综合多维评估和计算模型-
免疫生态系统进化,T细胞表观遗传和功能状态,以及TCR谱对不同
细胞死亡的类型将解开促进抗肿瘤免疫的机制。TCGA分析显示,Low
凋亡体成分APAF1和Caspase-9的表达与更好的生存结果有关,
提示caspase非依赖的mimtosis可能激活抗肿瘤免疫并提供生存益处。
在ccrcc。我们将通过对慢性肾细胞癌患者进行单核多组体和MxIF来评估这一假说。
比较ccRCC低表达与高凋亡体表达的样本以表征肿瘤免疫串扰。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
EMILY H CHENG其他文献
EMILY H CHENG的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('EMILY H CHENG', 18)}}的其他基金
Project III: Engineering immunogenic cell death in melanoma and renal cell carcinoma.
项目 III:工程化黑色素瘤和肾细胞癌中的免疫原性细胞死亡。
- 批准号:
10525194 - 财政年份:2022
- 资助金额:
$ 49.56万 - 项目类别:
Characterizing and Targeting BAX- and BAK-Dependent Cell Death in Cancer
癌症中 BAX 和 BAK 依赖性细胞死亡的表征和靶向
- 批准号:
10375572 - 财政年份:2021
- 资助金额:
$ 49.56万 - 项目类别:
Characterizing and Targeting BAX- and BAK-Dependent Cell Death in Cancer
癌症中 BAX 和 BAK 依赖性细胞死亡的表征和靶向
- 批准号:
10211264 - 财政年份:2021
- 资助金额:
$ 49.56万 - 项目类别:
Characterizing and Targeting BAX- and BAK-Dependent Cell Death in Cancer
癌症中 BAX 和 BAK 依赖性细胞死亡的表征和靶向
- 批准号:
10621724 - 财政年份:2021
- 资助金额:
$ 49.56万 - 项目类别:
Genetic Loss-of-Function Studies of SETD2 in Kidney Tumorigenesis
SETD2 在肾肿瘤发生中的遗传功能丧失研究
- 批准号:
10392931 - 财政年份:2018
- 资助金额:
$ 49.56万 - 项目类别:
Genetic Loss-of-Function Studies of SETD2 in Kidney Tumorigenesis
SETD2 在肾肿瘤发生中的遗传功能丧失研究
- 批准号:
9916771 - 财政年份:2018
- 资助金额:
$ 49.56万 - 项目类别:
相似海外基金
ホウ素中性子捕捉療法におけるabscopal effect機序の初期探索研究
硼中子俘获治疗远隔效应机制的初步探索性研究
- 批准号:
24K18767 - 财政年份:2024
- 资助金额:
$ 49.56万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Abscopal effect of 131I-MIBG therapy for refractory neuroblastoma
131I-MIBG 治疗难治性神经母细胞瘤的远隔效应
- 批准号:
20K22836 - 财政年份:2020
- 资助金额:
$ 49.56万 - 项目类别:
Grant-in-Aid for Research Activity Start-up
Local oncolytic adenovirotherapy inducing the direct abscopal effect via exosome
局部溶瘤腺病毒疗法通过外泌体诱导直接远隔效应
- 批准号:
20K17617 - 财政年份:2020
- 资助金额:
$ 49.56万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of a mechanism of abscopal effect -Innovative cancer treatment strategy-
阐明远隔效应的机制-创新的癌症治疗策略-
- 批准号:
18H02696 - 财政年份:2018
- 资助金额:
$ 49.56万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Elucidation for epigenetic mechanism of Abscopal effect in rectal cancer after CRT
阐明直肠癌 CRT 后远隔效应的表观遗传机制
- 批准号:
18K16279 - 财政年份:2018
- 资助金额:
$ 49.56万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The abscopal effect of nanosecond electric pulse tumor ablation and its enhancement for metastatic breast cancer
纳秒电脉冲肿瘤消融及其强化治疗转移性乳腺癌的远隔效应
- 批准号:
9756343 - 财政年份:2018
- 资助金额:
$ 49.56万 - 项目类别:
Consideration of effectiveness of intra-abdominal hyperthermia chemotherapy devised from abscopal effect
从远隔效应角度探讨腹腔热化疗的有效性
- 批准号:
18K08592 - 财政年份:2018
- 资助金额:
$ 49.56万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Development of a new cancer treatment method using semiconductor lasers and investigation of the abscopal effect
使用半导体激光器开发新的癌症治疗方法并研究远隔效应
- 批准号:
18K17222 - 财政年份:2018
- 资助金额:
$ 49.56万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
CT detection of primary and metastatic tumor and their treatment abscopal effect via radiation
原发性和转移性肿瘤的CT检测及其放射治疗远隔效应
- 批准号:
17K10489 - 财政年份:2017
- 资助金额:
$ 49.56万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Exploratory Optimization of Organs for Radiotherapy or Cancer Vaccination by Abscopal Effect
通过远隔效应探索性优化放疗或癌症疫苗接种的器官
- 批准号:
17K10473 - 财政年份:2017
- 资助金额:
$ 49.56万 - 项目类别:
Grant-in-Aid for Scientific Research (C)