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.
项目三.黑色素瘤和肾细胞癌中的工程免疫原性细胞死亡
实验负责人:Cheng
计算主管:Leslie
实验合作研究者:Li
项目摘要
最近批准免疫检查点阻断(ICB)在多种癌症类型中的应用彻底改变了癌症护理,
但只有一小部分患者获得持久的完全反应。因此,迫切需要
基于免疫疗法的新型治疗策略,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这样的策略之一。坏死下垂和
焦亡是程序性坏死的两种形式,是促炎性的并且可能是免疫原性的。相比之下,
线粒体凋亡通常被认为是免疫学沉默的。BCL-2家族蛋白是核心的
线粒体凋亡的调节因子。BAX和巴克一旦被仅含BH 3的分子激活,就会触发
线粒体外膜透化(MOMP),其释放细胞色素c以激活线粒体外膜。
溶酶体和半胱天冬酶。最近的范式转变发现表明,BAX/巴克激活在
半胱天冬酶的缺乏可以触发线粒体DNA通过一个称为
“线粒体内膜透化”(MIMP),其激活cGAS/STING途径和I型
干扰素应答这些发现表明,这种BAX/BAK依赖性,半胱天冬酶非依赖性细胞
死亡,我们称之为“mimptosis”,是高度炎症。在这里,我们设计了诱导性细胞死亡的模型,
小鼠黑色素瘤和透明细胞肾细胞癌的基因工程小鼠模型(GEMM)
(ccRCC)以比较体内对细胞凋亡、细胞凋亡、细胞凋亡和细胞坏死的免疫应答。我们
我们的目标是确定最具免疫原性的细胞死亡,不仅杀死癌细胞,而且还指导免疫系统。
系统,以增强ICB反应,并阐明潜在的分子机制,使用一个全面的
系统生物学方法在目标1中,我们将描述不同类型的工程
免疫原性细胞死亡(ICD)对肿瘤免疫生态系统动力学黑色素瘤使用整合的单细胞
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。
计算建模将定义免疫细胞基因表达和调控程序,以响应ICD
为改善ICB的治疗策略提供信息。在目标2中,我们将确定免疫原性细胞是否以及如何
消除肿瘤进展和转移并产生针对肿瘤再攻击的免疫记忆
在ccRCC的GEMM中。肿瘤的全面多维评估和计算建模-
免疫生态系统进化,T细胞表观遗传和功能状态,以及TCR库响应于不同的
不同类型的细胞死亡将解开促进抗肿瘤免疫的机制。TCGA分析显示,低
溶酶体成分APAF 1和Caspase-9的表达与更好的生存结果相关,
这表明半胱天冬酶非依赖性免疫缺陷可以激活抗肿瘤免疫并赋予生存益处,
在ccRCC。我们将通过在ccRCC患者中进行单核多组和MxIF来评估这一假设
样品来表征肿瘤免疫串扰,比较具有低相对于高溶酶体表达的ccRCC。
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)
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EMILY H CHENG其他文献
EMILY H CHENG的其他文献
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{{ 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:
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