Regulating Intratumoral Leukocytes to Improve Response to Chemotherapy
Regulating Intratumoral Leukocytes to Improve Response to Chemotherapy
批准号:
9031228
负责人:
Brian Ruffell
金额:
$24.9万
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
已结题
起止时间:
2015-04-01 至 2018-03-31
关键词:
AddressAdjuvantAdjuvant ChemotherapyAgonistBreast Cancer TreatmentBreast CarcinomaCD8B1 geneCarcinomaCell DeathCell physiologyCessation of lifeClinicalClinical TrialsCombination Drug TherapyDendritic CellsDendritic cell activationDiseaseDisease-Free SurvivalGenomicsHormone ReceptorHormonesImmuneImmune responseIn complete remissionIncidenceIndividualInfiltrationInterleukin-10Interleukin-12LeukocytesLymphocyteMalignant NeoplasmsMammary NeoplasmsMediatingModelingMolecularMusNeoadjuvant TherapyPathologicPatient MonitoringPatientsPhenocopyProductionRecruitment ActivityRecurrenceRefractoryRegimenRoleSolidSourceT cell responseT-Cell ProliferationT-LymphocyteTestingTransgenic MiceWomanbasechemotherapycytokinecytotoxicexperienceimprovedinsightinterleukin-10 receptormacrophagemalignant breast neoplasmmouse modelnovel therapeuticsoutcome forecastpreventreceptorresponsestandard of caretumorunpublished works
中文摘要
项目总结
大多数实体恶性肿瘤患者接受化疗方案,或在辅助或
新佐剂环境。对化疗的反应不仅仅取决于存在的基因组异常
在肿瘤内,因为它也取决于细胞毒性淋巴细胞的渗透和效应功能,基于
在多种癌症中CD8+T细胞的浸润与应答率有很强的临床相关性,以及
从可植入的小鼠肿瘤模型中支持功能作用的证据。增强CD8+T细胞
因此,化疗期间的反应有可能提高病理完全缓解率和
延长患者存活期。我们最近使用转基因小鼠乳腺模型进行了演示。
肿瘤相关巨噬细胞消除CD8+T细胞依赖的反应
化疗。在未发表的工作中,我们现在已经确定这种抑制活动源于
产生白介素10,因为巨噬细胞是肿瘤内白介素10的主要来源,以及
白细胞介素10受体(IL10R)阻断巨噬细胞拮抗剂在化疗中的作用
回应。虽然白介素10并不直接抑制CD8+T细胞的增殖或功能,但我们观察到
丹参治疗后瘤内树突状细胞浸润及白细胞介素12表达增加
联合化疗中的巨噬细胞拮抗剂。因此我们假设白介素10
抑制化疗诱导的细胞死亡后树突状细胞的激活,从而防止
肿瘤内CD8+T细胞的重新激活和为改善免疫反应提供一个易处理的靶点
化疗。为了检验这些假设,我们提出了以下具体目标:确定泛函
肿瘤内树突状细胞活化在调节IL10R化疗疗效中的意义
阻断;确定肿瘤内CD8+T细胞与招募的CD8+T细胞在介导
IL10R阻断后对化疗的反应;并比较抗肿瘤免疫反应的持久性
IL10R阻断和化疗联合免疫检查点阻断与联合应用
刺激性兴奋剂。
英文摘要
PROJECT SUMMARY
The majority of patients with solid malignancies undergo chemotherapeutic regimens either in the adjuvant or
neoadjuvant setting. Response to chemotherapy is not solely dependent upon the genomic aberrations present
within tumors, as it is also contingent upon the infiltration and effector function of cytotoxic lymphocytes, based
upon the strong clinical association of CD8+ T cell infiltration with response rates in multiple carcinomas, and
supporting evidence of a functional role from implantable mouse tumor models. Enhancing the CD8+ T cell
response during chemotherapy therefore has the potential to improve pathologic complete response rates and
extend patient survival. We have recently demonstrated using a transgenic mouse model of mammary
carcinoma that tumor-associated macrophages abrogate the CD8+ T cell-dependent response during
chemotherapy. In unpublished work, we have now identified that this suppressive activity is derived from
production of interleukin 10 (IL10), as macrophages are the primary source of interleukin 10 within tumors, and
IL10 receptor (IL10R) blockade phenocopies the effects of macrophage antagonists during a chemotherapeutic
response. While interleukin 10 does not directly suppress CD8+ T cell proliferation or function, we observe
increased infiltration of intratumoral dendritic cells and expression of interleukin 12 following treatment with
macrophage antagonists in combination chemotherapy. We therefore hypothesize that interleukin 10
suppresses activation of dendritic cells following chemotherapy-induced cell death, thereby preventing
reactivation of intratumoral CD8+ T cells and offering a tractable target for improving immune responses during
chemotherapy. To test these hypotheses we propose the following specific aims: Determine the functional
significance of intratumoral dendritic cell activation in regulating response to chemotherapy following IL10R
blockade; determine the functional contribution of intratumoral versus recruited CD8+ T cells in mediating
response to chemotherapy following IL10R blockade; and compare durability of anti-tumor immune responses
following IL10R blockade and chemotherapy in combination with immune-checkpoint blockade versus co-
stimulatory agonists.
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专著(0)
科研奖励(0)
会议论文
Regulation of dendritic cell function and tumor immunity by TIM-3
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批准号:10218098
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项目类别:
-
资助金额:$39.35万
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财政年份:2019
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负责人:Brian Ruffell
-
依托单位:
Regulation of dendritic cell function and tumor immunity by TIM-3
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批准号:10018832
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项目类别:
-
资助金额:$39.35万
-
财政年份:2019
-
负责人:Brian Ruffell
-
依托单位:
Regulation of dendritic cell function and tumor immunity by TIM-3
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批准号:10475053
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项目类别:
-
资助金额:$39.35万
-
财政年份:2019
-
负责人:Brian Ruffell
-
依托单位:
Regulation of dendritic cell function and tumor immunity by TIM-3
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批准号:10676810
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项目类别:
-
资助金额:$38.56万
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财政年份:2019
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负责人:Brian Ruffell
-
依托单位:
Regulating Intratumoral Leukocytes to Improve Response to Chemotherapy
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批准号:8790105
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项目类别:
-
资助金额:$13.14万
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财政年份:2014
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负责人:Brian Ruffell
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依托单位:
海外基金