Novel immune suppressive activities of Fas/CD95 in triple negative breast cancer
Fas/CD95 在三阴性乳腺癌中的新型免疫抑制活性
基本信息
- 批准号:10661817
- 负责人:
- 金额:$ 45.11万
- 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:2022-07-07 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:Antitumor ResponseBindingBinding ProteinsBiochemicalBiological AssayBreast Cancer CellC-terminalCD95 AntigensCancer EtiologyCellsCessation of lifeClinicClinicalComplementComplexDataEquilibriumFas Signaling PathwayGenetic RecombinationGenetic TranscriptionGenetically Engineered MouseGoalsGrowthImmuneImmune checkpoint inhibitorImmunocompetentImmunosuppressionImmunotherapyImplantIn VitroInduction of ApoptosisInfiltrationInflammatoryKiller CellsKnock-outKnockout MiceKnowledgeLigandsLymphocytic InfiltrateMalignant NeoplasmsMediatingModelingMolecularMouse Cell LineMouse StrainsMusMyeloid-derived suppressor cellsNF-Kappa B p65NF-kappa BNMR SpectroscopyNatural Killer CellsNatureNeoplasm MetastasisOutcomePatientsProductionPrognosisPrognostic FactorPublic HealthRoleSignal TransductionTNFRSF5 geneTNFRSF6 geneTestingTissuesTumor PromotionWomanWorkcancer cellcancer subtypescancer therapycrosslinkcytokinederepressiondesignimmune activationimmune checkpointimprovedin vivoinhibitormalignant breast neoplasmmolecular subtypesmouse modelneoplastic cellnovelp65peptidomimeticspermissivenessprogramsprotein complexreceptorrecruitscreeningsingle-cell RNA sequencingsmall molecule librariestargeted treatmenttriple-negative invasive breast carcinomatumortumor growthtumor microenvironmentubiquitin ligase
项目摘要
Summary
Among women, breast cancer (BC) is the most common malignancy, and the second leading cause of cancer
death. Patients with basal/triple negative BC (TNBC) have the poorest clinical outcome with no targeted
therapies available when compared to other molecular subtypes. Fas/CD95 is a well characterized death
receptor that in permissive cells mediates induction of apoptosis when stimulated by its cognate ligand, FasL. It
is now well established that Fas also has multiple nonapoptotic, tumor promoting functions. High Fas
expression is a negative prognostic factor for TNBC. We have previously demonstrated in multiple genetically
engineered mouse tumor models with tissue specific deletion of Fas that cancer cells maintain Fas expression
and without Fas tumors do not grow. However, some tumors still formed in these knock-out (KO) mice due to
‘escapers’ from Cre recombination. It remained unclear whether this activity of Fas was cell autonomous or
required cells of the tumor microenvironment. New preliminary data on a mouse model of TNBC now suggest
that tumor cell expressed Fas exerts an immune suppressive activity promoting recruitment of myeloid derived
suppressor cells (MDSCs) resulting in inhibition of tumor infiltration by natural killer (NK) cells. Most recently
we discovered, KPC2, a novel Fas interaction partner that binds to the C-terminal end and in unstimulated
TNBC cells sequesters both the NF-κB subunit p65 and KPC1, a ubiquitin ligase that degrades the p50
precursor p105. We found that when Fas is eliminated p105 gets degraded shifting the balance of NF-κB
subunits from repressive p50/p50 homodimers to transcriptionally active p50/p65 heterodimers. That in turn
unleashes production of a number of proinflammatory cytokines that regulate the recruitment of a number of
immune cells including NK cells. Based on these preliminary data we hypothesize that in TNBC Fas acts as a
novel immune check point for NK cells likely by remodeling the immune landscape, that a novel Fas bound
protein complex around KPC2 is responsible for this immune suppressive activity of Fas and finally, that
disrupting this interaction unleashes an antitumor activity that can be used to target TNBC cells. These
hypotheses will be studied in two specific aims: Specific Aim 1: Characterize immune suppressive activities of
Fas in triple negative breast cancer. Specific Aim 2: To determine how Fas expression suppresses a
proinflammatory program. The goal of this project is to characterize novel activities of Fas in promoting TNBC
growth and metastasis as well as its immune suppressive function on NK cells. The project will increase our
knowledge on the role of a complex and critical receptor/ligand signaling pair in cancer that has long been
misunderstood. Only recently has inhibition of FasL (and not its use) been recognized as a valuable option for
the treatment of cancer in the clinic. In TNBC our work now points at inhibiting the Fas receptor in addition to
its ligand. Finally, the novel immune suppressive activity of Fas provides a compelling rationale to combine
Fas/FasL inhibition with conventional checkpoint inhibitors for the treatment of TNBC.
总结
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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Marcus E. Peter其他文献
Expression of c-FLIP<sub>L</sub> and resistance to CD95-mediated apoptosis of monocyte-derived dendritic cells: inhibition by bisindolylmaleimide
- DOI:
10.1182/blood.v95.11.3478 - 发表时间:
2000-06-01 - 期刊:
- 影响因子:
- 作者:
Fabienne Willems;Zoulikha Amraoui;Nathalie Vanderheyde;Valérie Verhasselt;Ezra Aksoy;Carsten Scaffidi;Marcus E. Peter;Peter H. Krammer;Michel Goldman - 通讯作者:
Michel Goldman
Mapping of Ras-related GTP-binding proteins by GTP overlay following two-dimensional gel electrophoresis.
二维凝胶电泳后通过 GTP 覆盖图绘制 Ras 相关 GTP 结合蛋白。
- DOI:
- 发表时间:
1994 - 期刊:
- 影响因子:11.1
- 作者:
Lukas A. Huber;Oliver Ullrich;Y. Takai;Anne Lütcke;Paul Dupree;V. Olkkonen;H. Virta;M. J. D. Hoop;Kirill Alexandrov;Marcus E. Peter;Marino Zerial;Kai Simons - 通讯作者:
Kai Simons
AIDS and the death receptors.
艾滋病和死亡受体。
- DOI:
- 发表时间:
1997 - 期刊:
- 影响因子:6.7
- 作者:
Marcus E. Peter;A. Ehret;Christina Berndt;P. H. Krammer - 通讯作者:
P. H. Krammer
The two CD95 apoptosis signaling pathways may be a way of cells to respond to different amounts and/or forms of CD95 ligand produced in different tissues
这两条CD95凋亡信号通路可能是细胞对不同组织中产生的不同量和/或形式的CD95配体作出反应的一种方式
- DOI:
10.1038/sj.cdd.4400707 - 发表时间:
2000 - 期刊:
- 影响因子:12.4
- 作者:
Ingo Schmitz;Henning Walczak;P. H. Krammer;Marcus E. Peter - 通讯作者:
Marcus E. Peter
APO‐1(CD95)‐mediated apoptosis in Jurkat cells does not involve src kinases or CD45
Jurkat 细胞中 APO-1(CD95) 介导的细胞凋亡不涉及 src 激酶或 CD45
- DOI:
- 发表时间:
1995 - 期刊:
- 影响因子:3.5
- 作者:
B. Schraven;Marcus E. Peter - 通讯作者:
Marcus E. Peter
Marcus E. Peter的其他文献
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{{ truncateString('Marcus E. Peter', 18)}}的其他基金
Novel immune suppressive activities of Fas/CD95 in triple negative breast cancer
Fas/CD95 在三阴性乳腺癌中的新型免疫抑制活性
- 批准号:
10514907 - 财政年份:2022
- 资助金额:
$ 45.11万 - 项目类别:
DISE - a natural cancer surveillance mechanism - a new road to cancer therapy
DISE——天然癌症监测机制——癌症治疗新之路
- 批准号:
9313238 - 财政年份:2015
- 资助金额:
$ 45.11万 - 项目类别:
DISE - a natural cancer surveillance mechanism - a new road to cancer therapy
DISE——天然癌症监测机制——癌症治疗新之路
- 批准号:
10224839 - 财政年份:2015
- 资助金额:
$ 45.11万 - 项目类别:
DISE - a natural cancer surveillance mechanism - a new road to cancer therapy
DISE——天然癌症监测机制——癌症治疗新之路
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9753713 - 财政年份:2015
- 资助金额:
$ 45.11万 - 项目类别:
DICE - a natural cancer surveillance mechanism - a new road to cancer therapy
DICE——自然癌症监测机制——癌症治疗新之路
- 批准号:
9122387 - 财政年份:2015
- 资助金额:
$ 45.11万 - 项目类别:
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