Identifying Immune Mechanisms for Microbiota-Inhibition of Anti-PD-L1 Tumor Response
确定微生物群抑制抗 PD-L1 肿瘤反应的免疫机制
基本信息
- 批准号:10295768
- 负责人:
- 金额:$ 3.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-12-24 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAnimalsAntibioticsAntigensAntitumor ResponseApplications GrantsArchitectureBiological MarkersBiological Response ModifiersCD8-Positive T-LymphocytesCD8B1 geneCancer PatientCancer PrognosisCell physiologyCellsClinicalCombined Modality TherapyCommunitiesDataDendritic CellsDependenceGnotobioticGrantGrowthHematopoietic NeoplasmsHumanImmuneImmune responseImmune systemImmunityImmunooncologyImmunotherapyImpairmentInnate Immune SystemIntestinesKnowledgeLearningLesionLicensingLymphocyteLymphoid CellMalignant NeoplasmsMediatingMediator of activation proteinMetagenomicsMinorityModelingModificationMucous MembraneMusMyelogenousMyeloid Cell ActivationMyeloid CellsOrganismPaperPatient-Focused OutcomesPatientsPeripheralPharmaceutical PreparationsPhenotypePopulationProteomicsReportingResearchRoleSamplingSolidStudy modelsT cell responseT-Cell ActivationT-Cell ProliferationT-LymphocyteT-Lymphocyte SubsetsTherapeuticTransplantationTumor-Infiltrating LymphocytesVendorWorkadaptive immune responseanti-CTLA4anti-PD-1anti-PD-L1anti-PD-L1 therapyanti-tumor immune responseautoimmune toxicitybasecancer cellcancer immunotherapycancer therapycell killingcongenicdraining lymph nodegut microbiotahuman microbiotaimmune checkpointimmune checkpoint blockadeimprovedin vivomacrophagemelanomamicrobialmicrobial communitymicrobiotaneoplastic cellnew therapeutic targetpatient subsetspreventrational designresponsetranscriptometranscriptomicstumortumor growth
项目摘要
PROJECT SUMMARY
Immune checkpoint blockade is a recent cancer therapeutic strategy that has enabled durable responses in 15-
40% of patients for several cancers by licensing CD8+ tumor infiltrating lymphocytes to kill tumor cells. Despite
dramatically altering the clinical course in a subset of patients, these drugs fail to elicit durable response in the
majority of cancer patients. The human microbiota is thought to regulate immune tone or responsiveness, and
thus is a promising, modifiable target to improve checkpoint blockade response rates. Indeed, response rates
for epidermal malignancies to anti-PD-1 have been associated with fecal microbial diversity, and patients’ prior
use of antibiotics. Moreover, particular bacterial isolates have been identified in mice that can
disproportionally contribute to tumor immune responses following anti-CTLA-4 and anti-PD-L1 therapy.
While the potential importance of microbiota manipulation for checkpoint blockade response is clear, much
work remains to be done to determine how these microbiota-dependent immune responses to cancer are
generated and maintained. To begin understanding how the microbiota-immune interface in the gut can
contribute to the immune activity and anti-PD-L1 response of non-mucosal malignancy, I have established a
humanized gnotobiotic model of anti-PD-L1 treated melanoma. I have demonstrated that a defined microbial
community can inhibit B16 melanoma response to anti-PD-L1. This grant aims to dissect the yet
unknown mechanisms that mediate this microbiota-dependent inhibition of tumor response to
anti-PD-L1 by evaluating the functions and phenotypes of several immune cell populations in the
tumor and tumor draining lymph node. Aim 1—Based on my preliminary data we have selected two defined
microbial communities that result in contrasting tumor growth rates when colonized into germfree, B16
melanoma-bearing mice. I aim to evaluate the influence of intestinal microbiota on anti-tumor T cell
responses following checkpoint blockade therapy by exploring possible differences in tumor-immune
architecture, modifications to T cell proliferation and killing of tumor cells, depletion of key T cell subsets and
regulators in vivo, and metagenomic profiling before and after anti-PD-L1 treatment. Aim 2—The adaptive
immune response is dependent upon priming and activation by myeloid cells, which in turn are modified by
microbial sensing machinery. We hypothesize that alterations in myeloid cell functions and
phenotypes regulate the adaptive response to anti-PD-L1. To evaluate these cells I will preform
transcriptomic and proteomic analysis of macrophages and dendritic cells in the tumor and draining lymph
node, assess response causal dependency through myeloid subset depletion, and evaluate the priming ability of
dendritic cells from responding and nonresponding gnotobiotic mice. By studying these gnotobiotic animals
with different clinical responses to checkpoint blockade, we hope to uncover the mechanisms that contribute to
checkpoint blockade response, and possibly identify new immunotherapy targets or biomarkers.
项目摘要
免疫检查点阻断是一种最近的癌症治疗策略,它使15- 20岁的人能够获得持久的反应。
40%的几种癌症的患者通过CD 8+肿瘤浸润淋巴细胞来杀死肿瘤细胞。尽管
虽然这些药物在一部分患者中显著改变了临床过程,但这些药物未能在患者中引起持久的反应。
大多数癌症患者。人类微生物群被认为调节免疫张力或反应性,
因此是一个有希望的、可修改的目标,以提高检查点封锁响应率。事实上,
对于表皮恶性肿瘤,抗PD-1与粪便微生物多样性相关,患者既往
使用抗生素。此外,已经在小鼠中鉴定出特定的细菌分离物,
在抗CTLA-4和抗PD-L1治疗后促进肿瘤免疫应答。
虽然微生物群操纵对于检查点阻断响应的潜在重要性是清楚的,但许多微生物群操纵对于检查点阻断响应的潜在重要性是显而易见的。
我们仍有工作要做,以确定这些微生物群依赖的癌症免疫反应是如何发生的。
生成和维护。为了开始了解肠道中的微生物-免疫界面如何
有助于非粘膜恶性肿瘤的免疫活性和抗PD-L1应答,我已经建立了一个
抗PD-L1治疗的黑色素瘤的人源化gnotobiotic模型。我已经证明了一种特定的微生物
抗PD-L1抗体可抑制B16黑色素瘤细胞对PD-L1抗体的应答。这项资助旨在剖析
介导这种微生物群依赖性抑制肿瘤反应的未知机制是
抗PD-L1通过评估几种免疫细胞群体的功能和表型,
肿瘤和肿瘤引流淋巴结。目标1-根据我的初步数据,我们选择了两个定义
微生物群落,当定殖到无菌环境中时,导致相反的肿瘤生长速率,B16
荷黑色素瘤小鼠。目的是评价肠道菌群对抗肿瘤T细胞的影响,
检查点阻断治疗后的反应,通过探索肿瘤免疫的可能差异,
结构、对T细胞增殖的修饰和肿瘤细胞的杀伤、关键T细胞亚群的耗竭以及
体内调节剂,以及抗PD-L1治疗前后的宏基因组分析。目标2-适应性
免疫应答依赖于髓样细胞的引发和活化,髓样细胞又被
微生物传感器我们假设骨髓细胞功能的改变和
表型调节对抗PD-L1的适应性应答。为了评估这些细胞,
肿瘤和引流淋巴中巨噬细胞和树突状细胞的转录组学和蛋白质组学分析
节点,通过骨髓亚群耗竭评估应答因果依赖性,并评估
树突状细胞从响应和非响应gnotobiotic小鼠。通过研究这些知生动物
通过对检查点阻断的不同临床反应,我们希望揭示有助于
检查点阻断反应,并可能识别新的免疫治疗靶标或生物标志物。
项目成果
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