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 人们。结直肠肿瘤通常在晚期才被发现，而治疗往往会失败。免疫疗法是 彻底改变了多种癌症的治疗方法，但仅对一小部分结直肠癌患者有效。 因此，迫切需要改进 CRC 的治疗方法。结直肠肿瘤从肠道生长 上皮细胞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 免疫反应，是肿瘤免疫治疗功效的关键调节剂。使用鼠标模型 CRC (AOM/DSS) 我们展示了单一细菌分类单元的定植：肝螺杆菌，在肿瘤后 已经发育，导致肿瘤负荷和大小减少。肝螺杆菌的数量也有所增加， 结直肠肿瘤旁边的第三淋巴结构 (TLS) 的大小和组织。 TLS 的存在是 与结直肠癌患者的积极结果相关，但它们如何提高抗肿瘤免疫力并不清楚 已知。肝螺杆菌依赖性肿瘤减少依赖于 CD4 T 细胞和 B 细胞，但不依赖于 CD8 T 细胞。 大多数肝螺杆菌特异性 CD4+ T 细胞分化为滤泡辅助性 T (TFH) 细胞并定位于 TLS。 重要的是，CD4cre Bcl6flox 小鼠无法形成 TFH 细胞，也无法形成 TLS 或控制 CRC 生长， 但肝螺杆菌特异性 CD4+ T 细胞的转移完全恢复了抗肿瘤反应。我们的假设 Hhep 独特的粘液定植特性导致抗 Hhep TFH 的激活，并与 B 相互作用 细胞诱导瘤周 TLS 形成。结肠 TLS 充当激活抗肿瘤药物的平台 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 这个假设有两个目的。首先，我们将识别基因和行为（例如粘液/上皮定植） 与螺杆菌相关的结直肠癌控制有关。接下来我们将关联 TLS、TFH 和 人类结直肠癌患者体内的 B 细胞具有特定的粘液和肿瘤驻留细菌。最后，我们将使用鼠标 模型来确定 TLS 是否可以作为更有效激活抗肿瘤 T 细胞和 B 细胞的平台。 总之，我们的建议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 支持反攻击的机制 肿瘤免疫反应可用于制定抗结直肠癌治疗方法。如果成功的话我们 可以确定合理修改微生物组以增加抗肿瘤免疫力的机制。