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

• 批准号: 10585344
• 负责人: Timothy Wesley Hand
• 金额: $ 57.82万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10585344
• 关键词: Antibodies; Antibody Formation; Antigen Presentation; Antitumor Response; B-Lymphocytes; Bacteria; Behavior; C57BL/6 Mouse; CD4 Positive T Lymphocytes; Cancer Etiology; Cell Communication; Cells; Cessation of life; Colitis associated colorectal cancer; Colon; Colonic Neoplasms; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Dendritic Cells; Development; Disease; Epithelium; Failure; Genes; Growth; Helicobacter; Helicobacter hepaticus; Helper-Inducer T-Lymphocyte; Home; Human; Immune; Immune response; Immunity; Immunotherapy; Incidence; Inflammation; Intestines; Invaded; Knock-out; Location; MHC Class II Genes; Malignant Neoplasms; Measures; Mediator; Microsatellite Instability; Modeling; Mucous body substance; Mus; NK Cell Activation; Natural Killer Cells; Outcome; Patient-Focused Outcomes; Patients; Persons; Property; Rectal Cancer; Rectal Neoplasms; Sampling; Shapes; Structure; Structure of germinal center of lymph node; T cell differentiation; T-Lymphocyte; Taxon; Testing; Therapeutic; Tumor Antigens; Tumor Burden; Tumor Immunity; anti-tumor immune response; cancer type; colon bacteria; colon cancer patients; colon microbiota; colorectal cancer treatment; gut microbiome; immunogenic; improved; intestinal epithelium; melanoma; microbiome; microbiome composition; microbiota; model development; mouse model; murine colitis; neoplasm immunotherapy; tertiary lymphoid organ; tumor; tumor growth

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.

抽象的 结直肠癌（CRC）是与癌症相关死亡的主要原因，其发病率在年轻人中升高 人们。在治疗通常失败的后期，通常会检测到结直肠肿瘤。免疫疗法是 革命性的治疗多种类型的癌症，但仅对一小部分CRC患者有效。 因此，对于改善CRC的疗法的迫切需要。结直肠肿瘤从肠道生长 上皮并与结肠微生物群相互作用。 CRC与组成的变化有关 促进炎症和肿瘤生长的菌群。微生物群还可以塑造结肠T和B细胞 免疫反应，是肿瘤免疫疗法功效的关键调节剂。使用鼠标模型 CRC（AOM/DSS）我们表明，单个细菌分类群的定植：螺旋杆菌肝杆菌，肿瘤之后 已经开发出来，导致肿瘤负担和大小减轻。 H. Hepaticus也增加了数量， 大肠肿瘤旁边的三级淋巴结构（TLS）的大小和组织。 TLS的存在是 与CRC患者的阳性结果相关，但是他们如何作用增加抗肿瘤免疫力不是 已知。 H.肝依赖性肿瘤的减少取决于CD4 T细胞和B细胞，而不是CD8 T细胞。 大多数肝癌特异性CD4+ T细胞分化为T卵泡辅助器（TFH）细胞，并将其定位在TLS中。 重要的是，无法形成TFH细胞的CD4CRE BCL6FLOX小鼠也未能形成TLS或控制CRC生长， 但是，肝素特异性CD4+ T细胞的转移完全恢复了抗肿瘤反应。我们的假设 是HHEP的独特粘液定植特性导致与B相互作用的抗HHEP TFH激活 细胞诱导肿瘤周围的TLS形成。然后结肠TL充当激活抗肿瘤的平台 CD4+ T细胞，NK细胞和B细胞侵入肿瘤以支持有效的抗肿瘤免疫。我们将测试 这个假设在两个目标中。首先，我们将确定基因和行为（例如粘液/上皮定植） 与对CRC相关的螺旋细菌相关的控制。接下来，我们将将TLS，TFH和 人类CRC患者的B细胞患有特定粘液和肿瘤常见细菌。最后，我们将使用鼠标 模型以确定TLS是否充当抗肿瘤T和B细胞更有效激活的平台。 我们的建议在一起有可能确定应针对的关键细菌成分 增强抗肿瘤免疫力和结肠TLS。此外，我们可以确定TLS支持抗抗的机制 可用于制定治疗性抗CRC方法的肿瘤免疫反应。如果成功的话 可以确定合理修改微生物组以增加抗肿瘤免疫力的机制。