Identifying the mechanism of anti-colorectal immunity induced by mucoinvasive colonic bacteria
确定粘膜侵袭性结肠细菌诱导的抗结直肠免疫机制
基本信息
- 批准号:10585344
- 负责人:
- 金额:$ 57.82万
- 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:2022-12-01 至 2027-11-30
- 项目状态:未结题
- 来源:
- 关键词:AntibodiesAntibody FormationAntigen PresentationAntitumor ResponseB-LymphocytesBacteriaBehaviorC57BL/6 MouseCD4 Positive T LymphocytesCancer EtiologyCell CommunicationCellsCessation of lifeColitis associated colorectal cancerColonColonic NeoplasmsColorectalColorectal CancerColorectal NeoplasmsDendritic CellsDevelopmentDiseaseEpitheliumFailureGenesGrowthHelicobacterHelicobacter hepaticusHelper-Inducer T-LymphocyteHomeHumanImmuneImmune responseImmunityImmunotherapyIncidenceInflammationIntestinesInvadedKnock-outLocationMHC Class II GenesMalignant NeoplasmsMeasuresMediatorMicrosatellite InstabilityModelingMucous body substanceMusNK Cell ActivationNatural Killer CellsOutcomePatient-Focused OutcomesPatientsPersonsPropertyRectal CancerRectal NeoplasmsSamplingShapesStructureStructure of germinal center of lymph nodeT cell differentiationT-LymphocyteTaxonTestingTherapeuticTumor AntigensTumor BurdenTumor Immunityanti-tumor immune responsecancer typecolon bacteriacolon cancer patientscolon microbiotacolorectal cancer treatmentgut microbiomeimmunogenicimprovedintestinal epitheliummelanomamicrobiomemicrobiome compositionmicrobiotamodel developmentmouse modelmurine colitisneoplasm immunotherapytertiary lymphoid organtumortumor growth
项目摘要
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related death and its incidence is on the rise in young
people. Colorectal tumors are often detected at late stages where therapy often fails. Immunotherapy is
revolutionizing the treatment of many types of cancer but is only effective for a very small subset of CRC patients.
Thus, there is a critical need for improved therapies for CRC. Colorectal tumors grow from the intestinal
epithelium and interact with the colonic microbiota. CRC has been associated with shifts in the composition of
the microbiota that promote inflammation and tumor growth. The microbiota can also shape colonic T and B cell
immune responses and is a critical modulator of the efficacy of tumor immunotherapy. Using a mouse model of
CRC (AOM/DSS) we show that colonization with a single bacterial taxon: Helicobacter hepaticus, after tumors
have already developed, leads to a reduction in tumor burden and size. H. hepaticus also increased the number,
size and organization of Tertiary lymphoid structures (TLS) next to colorectal tumors. The presence of TLS is
associated with positive outcomes in CRC patients, but how they act to increase anti-tumor immunity is not
known. H. hepaticus-dependent tumor reduction depended upon CD4 T cells and B cells but not CD8 T cells.
Most H. hepaticus-specific CD4+ T cells differentiated into T Follicular Helper (TFH) cells and localized in TLS.
Importantly, CD4cre Bcl6flox mice, that cannot form TFH cells, also failed to either form TLS or control CRC growth,
but transfer of H. hepaticus-specific CD4+ T cells completely restored the anti-tumor response. Our hypothesis
is that the distinct mucus colonization properties of Hhep leads to activation of anti-Hhep TFH that interact with B
cells to induce peri-tumoral TLS formation. Colonic TLS then act as platforms for the activation of anti-tumor
CD4+ T cells, NK cells and B cells which invade the tumor to support effective anti-tumor immunity. We will test
this hypothesis in two aims. First, we will identify the genes and behavior, (such as mucus/epithelial colonization)
associated with Helicobacter-associated control over CRC. Next we will correlate the presence of TLS, TFH and
B cells in human CRC patients with specific mucus and tumor resident bacteria. Finally, we will use our mouse
models to identify whether TLS serve as platforms for more effective activation of anti-tumor T and B cells.
Together, our proposal has the potential to identify the key bacterial components that should be targeted to
augment anti-tumor immunity and colonic TLS. Further we may identify mechanisms by which TLS support anti-
tumor immune responses which could be used to formulate therapeutic anti-CRC approaches. If successful we
could identify mechanisms to rationally modify the microbiome to increase anti-tumor immunity.
摘要
结直肠癌(CRC)是癌症相关死亡的主要原因,其发病率在年轻人中呈上升趋势。
人结直肠肿瘤通常在治疗失败的晚期才被发现。免疫疗法是
这种方法彻底改变了许多类型的癌症的治疗,但仅对CRC患者的非常小的子集有效。
因此,迫切需要改善CRC的疗法。结直肠肿瘤从肠道生长
并与结肠微生物群相互作用。CRC与以下成分的变化有关:
促进炎症和肿瘤生长的微生物群。微生物群还可以塑造结肠T和B细胞
免疫应答,并且是肿瘤免疫治疗功效的关键调节剂。使用小鼠模型,
CRC(AOM/DSS),我们表明,与一个单一的细菌类群:肝螺杆菌定植,肿瘤后
已经发展,导致肿瘤负荷和大小的减少。H.肝细胞也增加了数量,
结直肠肿瘤旁三级淋巴结构(TLS)的大小和组织。TLS的存在是
与结直肠癌患者的积极结局相关,但它们如何增加抗肿瘤免疫力并不重要。
知道的H.肝依赖性肿瘤缩小依赖于CD 4 T细胞和B细胞,而不依赖于CD 8 T细胞。
大多数H。肝脏特异性CD 4 + T细胞分化为T滤泡辅助细胞(TFH)并定位于TLS中。
重要的是,不能形成TFH细胞的CD 4cre Bcl 6 flox小鼠也不能形成TLS或控制CRC生长,
但H.肝特异性CD 4 + T细胞完全恢复了抗肿瘤应答。我们的假设
Hhep独特的粘液定植特性导致与B相互作用的抗Hhep TFH的活化
细胞以诱导肿瘤周围TLS形成。然后结肠TLS充当激活抗肿瘤的平台
CD 4 + T细胞、NK细胞和B细胞,它们侵入肿瘤以支持有效的抗肿瘤免疫。我们将测试
这个假设有两个目的。首先,我们将确定基因和行为,(如粘液/上皮定植)
与螺杆菌相关的CRC控制相关。接下来,我们将关联TLS、TFH和
人CRC患者中的B细胞与特定粘液和肿瘤驻留细菌。最后,我们将使用鼠标
模型,以确定TLS是否作为更有效地激活抗肿瘤T和B细胞的平台。
总之,我们的建议有可能确定应该针对的关键细菌成分,
增强抗肿瘤免疫和结肠TLS。此外,我们可以确定TLS支持反
肿瘤免疫应答,其可用于制定治疗性抗CRC方法。如果成功,我们
可以确定合理修饰微生物组以提高抗肿瘤免疫力的机制。
项目成果
期刊论文数量(0)
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Timothy Wesley Hand其他文献
Timothy Wesley Hand的其他文献
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{{ truncateString('Timothy Wesley Hand', 18)}}的其他基金
Investigating the tissue location and protective function of oral vaccine-specific tissue resident memory CD4 T cells
研究口服疫苗特异性组织驻留记忆 CD4 T 细胞的组织定位和保护功能
- 批准号:
10646930 - 财政年份:2023
- 资助金额:
$ 57.82万 - 项目类别:
Mechanisms of maternal Immunoglobulin A control over the neonatal microbiota and the development of Necrotizing Enterocolitis.
母体免疫球蛋白 A 控制新生儿微生物群和坏死性小肠结肠炎发展的机制。
- 批准号:
10312104 - 财政年份:2020
- 资助金额:
$ 57.82万 - 项目类别:
Mechanisms of maternal Immunoglobulin A control over the neonatal microbiota and the development of Necrotizing Enterocolitis.
母体免疫球蛋白 A 控制新生儿微生物群和坏死性小肠结肠炎发展的机制。
- 批准号:
9883292 - 财政年份:2020
- 资助金额:
$ 57.82万 - 项目类别:
Mechanisms of maternal Immunoglobulin A control over the neonatal microbiota and the development of Necrotizing Enterocolitis.
母体免疫球蛋白 A 控制新生儿微生物群和坏死性小肠结肠炎发展的机制。
- 批准号:
10541105 - 财政年份:2020
- 资助金额:
$ 57.82万 - 项目类别:
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