Understanding the impact of chemotherapy on breast cancer metastasis and immune function in the liver
了解化疗对乳腺癌转移和肝脏免疫功能的影响
基本信息
- 批准号:10638917
- 负责人:
- 金额:$ 51.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-07 至 2028-08-31
- 项目状态:未结题
- 来源:
- 关键词:Adjuvant ChemotherapyAffectAnthracyclineBar CodesBiopsy SpecimenBrainBreast Cancer CellBreast Cancer PatientBreast Cancer therapyBreast biopsyBreast cancer metastasisCD8-Positive T-LymphocytesCell physiologyCellsChemotherapy-Oncologic ProcedureClinicalClone CellsCombination Drug TherapyCyclophosphamideCytotoxic T-LymphocytesDataData SetDetectionDiagnosisDrug resistanceFDA approvedGoalsHeterogeneityImmuneImmune checkpoint inhibitorImmune systemImmunofluorescence ImmunologicImmunosuppressionImpairmentInvestigationKnowledgeLifeLiverLungLymphocyteMalignant NeoplasmsMetastatic Neoplasm to the LiverMetastatic Neoplasm to the LungMethodsModelingMolecularMusNatural Killer CellsNeoadjuvant TherapyNeoplasm MetastasisOperative Surgical ProceduresOrganPatient imagingPatientsPre-Clinical ModelPrimary NeoplasmPrior ChemotherapyProcessPrognosisProliferatingPropertyRadiationResistanceSamplingSiteSpecimenStainsT-LymphocyteTestingTissue SampleTissuesTreatment ProtocolsTumor ImmunityTumor-infiltrating immune cellsWorkbody systemcancer cellchemotherapyclinical developmentcohortdesigneffective therapyfitnesshigh dimensionalityimmune functionimmune system functionimmunosuppressedimprovedmalignant breast neoplasmmouse modelmultiple omicsneoplastic cellnew technologynovel therapeutic interventionperipheral bloodpre-clinicalpreventreceptorresponsestandard caresuccesstaxanetranscriptome sequencingtreatment strategytriple-negative invasive breast carcinomatumortumor growthtumor heterogeneitytumor microenvironmenttumor progressiontumor-immune system interactions
项目摘要
Project Summary
Despite treatment with neoadjuvant chemotherapy, 30-40% of patients diagnosed with early-stage triple-
negative breast cancer (TNBC) develop metastasis and die of their cancer. Part of standard treatment for TNBC
includes anthracycline-cyclophosphamide and taxane-based (AC-T) chemotherapy, radiation, and surgery.
Combination chemotherapy with immune checkpoint inhibitors (ICI) that target T-cell inhibitory receptors are now
FDA-approved for early stage and metastatic TNBC. Despite promising trial results, most patients with metastatic
TNBC do not experience durable long-lasting benefits, particularly those whose tumors progressed on prior
chemotherapy. Although proliferating cancer cells are the intended targets, systemic chemotherapy clearly
impacts other organ systems. This includes detrimental effects on the immune system, such as elimination of
cytotoxic T cells. Thus, if chemotherapy impairs anti-tumor immune cells, it would limit ICI efficacy. A major
challenge to the field is that we do not understand how chemotherapy impacts immune function or tumor cell
fitness in metastatic microenvironments. In our TNBC mouse models, AC-T chemotherapy reduced primary
tumor growth and lung metastasis. Surprisingly, liver metastasis, which is a predominant metastatic site in TNBC
patients, was significantly enhanced in the AC-T-treated mice. We also observed markers of immunosuppression
in the liver after chemotherapy in both our mouse models and clinical samples. We hypothesize that the liver is
specifically immunosuppressed by chemotherapy, thus making the liver more hospitable for TNBC metastasis
and reducing ICI efficacy. Our objective is to understand how chemotherapy impacts the liver immune
microenvironment and TNBC liver metastasis, and to identify pre-clinical strategies that prevent liver
immunosuppression and metastasis.
We will use our TNBC lung metastasis models and our highly sensitive molecular barcoding method for
metastasis detection. We will identify tumor cell clones that grow in metastatic sites and if the clonal composition
changes in response to chemotherapy treatment. We will also determine whether those clones are inherently
sensitive/resistant to chemotherapy or if their response to chemotherapy relies on the metastatic
microenvironment. We will perform high dimensional immune-profiling of primary tumors and liver from
chemotherapy-treated tumor-free and tumor-bearing mice using single cell multi-omic approaches. We will
assess immune function of cells derived from metastatic sites in the mouse models. We will validate our findings
by multiplex immunofluorescence staining on patient biopsy samples taken from metastatic sites. We will identify
treatment regimens that target tumor cells while protecting anti-tumor immune cells. Our proposed studies will
deepen our understanding of the systemic effects of chemotherapy, not only on breast cancer cells that spread
to various organs but also on immune cells in those organs. Success in our line of investigation will identify new
treatment approaches that are effective against breast cancer but do not diminish critical immune cells.
项目总结
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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Sandra S McAllister其他文献
Sandra S McAllister的其他文献
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{{ truncateString('Sandra S McAllister', 18)}}的其他基金
Understanding how the aging hematopoietic system affects cancer progression
了解衰老的造血系统如何影响癌症进展
- 批准号:
8769009 - 财政年份:2014
- 资助金额:
$ 51.02万 - 项目类别:
Understanding How Breast Cancers Activate and Respond to the Systemic Environment
了解乳腺癌如何激活和响应全身环境
- 批准号:
8437610 - 财政年份:2012
- 资助金额:
$ 51.02万 - 项目类别:
Understanding How Breast Cancers Activate and Respond to the Systemic Environment
了解乳腺癌如何激活和响应全身环境
- 批准号:
9315710 - 财政年份:2012
- 资助金额:
$ 51.02万 - 项目类别:
Understanding How Breast Cancers Activate and Respond to the Systemic Environment
了解乳腺癌如何激活和响应全身环境
- 批准号:
8547035 - 财政年份:2012
- 资助金额:
$ 51.02万 - 项目类别:
Understanding How Breast Cancers Activate and Respond to the Systemic Environment
了解乳腺癌如何激活和响应全身环境
- 批准号:
8706094 - 财政年份:2012
- 资助金额:
$ 51.02万 - 项目类别:
Understanding How Breast Cancers Activate and Respond to the Systemic Environment
了解乳腺癌如何激活和响应全身环境
- 批准号:
9107405 - 财政年份:2012
- 资助金额:
$ 51.02万 - 项目类别:
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