Role of microbiota in therapy to ovarian cancer

微生物群在卵巢癌治疗中的作用

• 批准号: 10115635
• 负责人: Troy D Randall
• 金额: $ 42.61万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-10 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115635
• 关键词: Address; Adipose tissue; Affect; Anti-Inflammatory Agents; Antitumor Response; Autoimmune Diseases; Bacteria; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Maintenance; Cells; Characteristics; Data; Dermal; Development; Due Process; Effectiveness; Effector Cell; Epithelial Cells; Family; Germ-Free; Greater sac of peritoneum; Growth; Immune; Immune checkpoint inhibitor; Immune system; Immunity; Impairment; Implant; Inflammation; Inflammatory; Inflammatory Response; Interleukin-17; Link; Location; Maintenance; Malignant neoplasm of ovary; Mediating; Metastatic Malignant Neoplasm to the Ovary; Modeling; Mus; Myeloid Cells; Neoplasm Metastasis; Omentum; Organ; PD-1 blockade; PPAR alpha; Pathway interactions; Peripheral; Peritoneal; Peroxisome Proliferator-Activated Receptors; Play; Population; Property; Publishing; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Role; Series; Site; Spleen; Stress; Surface; T cell response; Testing; Tumor Antigens; Tumor Immunity; Visceral; Volatile Fatty Acids; Work; adipocyte differentiation; allergic response; antitumor effect; base; cancer therapy; cell killing; chemotherapy; commensal bacteria; design; experimental study; gastrointestinal epithelium; gut bacteria; gut microbiota; immunogenic; implantation; intestinal epithelium; lymph nodes; microbial; microbiota; mouse model; neoplastic cell; novel strategies; ovarian neoplasm; prevent; programmed cell death protein 1; receptor; recruit; response; therapy outcome; transcription factor; tumor

This proposal is submitted in response to the RFA, “Research answers to NCI's provocative questions”, in particular, question 10, which asks, How do microbiota affect the response to cancer therapies? Our preliminary data show that when tumor cells colonize the omentum, a fatty tissue in the peritoneal cavity, they trigger a profound Treg-mediated tolerogenic response that prevents tumor-specific CD8 T cells from clearing the tumor. Interestingly, this activity is specific for the omentum and involves a subset of Tregs known as visceral-adipose tissue (VAT)-associated Tregs. VAT-associated Tregs uniquely express the transcription factor PPARg and also express the ST2 component of the IL-33 receptor on their surface. These cells are found exclusively in adipose tisses and are not found in conventional lymhoid organs (like the spleen and lymph nodes) and are not found in peripheral sites. Importantly, VAT-associated Tregs are found in the omentum, which is the site of ovarian cancer metastasis. In additioin to showing that VAT-associated Tregs profoundly impair immunity to tumors that colonize the omentum, we also found that this activity is completely dependent on gut microbiota. As a result, VAT-associated Treg activity is impaired and anti-tumor immunity is restored in the omenta of germ-free mice. These results are surprising, since published data show that microbiota promote (rather than prevent) the anti-tumor effect of chemotherapy. These results were explained by the ability of chemotherapy to compromise the gut epithelium, allowing the translocation of microbiota and thereby triggering an IL-17 response, which facilitates the effects of chemotherapy on the clearance of tumors. Based on these data, the central hypothesis of this proposal is that the microbiota play opposing roles in promoting the immune suppressive Tregs under steady state conditions and by promoting the immune stimulatory Th17 responses following chemotherapy. Moreover, these types of responses are location dependent, with VAT-associated Tregs residing and responding primarily in fatty tissues like the omentum. Thus, therapy for ovarian cancer, which routinely metastasizes to the omentum, may have different outcomes than therapy to tumors in other locations. The experiments in this application test this hypothesis using a spontaneous mouse model of ovarian cancer and determine the mechanistic links between the gut microbiota and immunity in the peritoneal cavity using and ectopic model of ovarian cancer.

该建议是根据RFA提交的 特别是，问题10，问：微生物群如何影响对癌症疗法的反应？我们的 初步数据表明，当肿瘤细胞在腹膜腔中定居Omentum时，它们时 触发深刻的Treg介导的耐受性反应，可防止肿瘤特异性CD8 T细胞清除 肿瘤。有趣的是，该活动是针对大脑特异性的，涉及一部分Tregs 内脏 - 脂肪组织（增值税）相关的Treg。与增值税相关的tregs独特地表达转录 因子PPARG，并在其表面表达IL-33受体的ST2成分。这些细胞是 仅在脂肪组织中发现，在常规淋巴机器人器官中没有发现（例如脾脏和 淋巴结），在外周部位未发现。重要的是，在 Omentum，这是卵巢癌转移的位置。为了显示增值税相关的Tregs 深刻损害了对膜的肿瘤的免疫学，我们还发现这种活动是完全的 取决于肠道菌群。结果，与增值税相关的Treg活性受到损害，抗肿瘤免疫史 恢复在无菌小鼠的Omenta中。这些结果令人惊讶，因为发布的数据表明 微生物群促进（而不是预防）化学疗法的抗肿瘤作用。这些结果解释了 通过化学疗法损害肠道上皮的能力，允许微生物群的易位 从而触发IL-17反应，这有助于化学疗法对清除肿瘤的影响。 基于这些数据，该提议的核心假设是微生物群在 在稳态条件下促进免疫抑制性Treg并通过促进免疫 化学疗法后的刺激性Th17反应。而且，这些类型的响应是位置 依赖性，与增值税相关的Treg居住并主要在肥大组织等脂肪组织中做出反应。 那是卵巢癌的治疗，通常会转移到omentum的疗法，可能会有不同的结果 比在其他位置对肿瘤进行治疗。此应用程序中的实验检验了该假设的 卵巢癌的自发小鼠模型，并确定肠道菌群之间的机械联系 使用卵巢癌的腹膜腔和生态模型中的免疫力。

项目成果

Class I histone deacetylase inhibition promotes CD8 T cell activation in ovarian cancer.

• DOI: 10.1002/cam4.3337
• 发表时间: 2021-01
• 期刊: Cancer medicine
• 影响因子: 4
• 作者: McCaw TR;Goel N;Brooke DJ;Katre AA;Londoño AI;Smith HJ;Randall TD;Arend RC
• 通讯作者: Arend RC

Neutralization of TGFβ Improves Tumor Immunity and Reduces Tumor Progression in Ovarian Carcinoma.

• DOI: 10.1158/1535-7163.mct-20-0412
• 发表时间: 2021-03
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Roane BM;Meza-Perez S;Katre AA;Goldsberry WN;Randall TD;Norian LA;Birrer MJ;Arend RC
• 通讯作者: Arend RC

Revisiting entinostat as an immune-potentiating adjuvant.

重新审视恩替司他作为免疫增强佐剂的作用。

• DOI: 10.18632/oncotarget.26453
• 发表时间: 2018
• 期刊: Oncotarget
• 作者: McCaw,TylerR;Randall,TroyD;Arend,RebeccaC
• 通讯作者: Arend,RebeccaC

Specialized immune responses in the peritoneal cavity and omentum.

• DOI: 10.1002/jlb.5mir0720-271rr
• 发表时间: 2021-04
• 期刊: Journal of leukocyte biology
• 影响因子: 5.5
• 作者: Liu M;Silva-Sanchez A;Randall TD;Meza-Perez S
• 通讯作者: Meza-Perez S

Enhancing anticancer activity of checkpoint immunotherapy by targeting RAS.

• DOI: 10.1002/mco2.10
• 发表时间: 2020-09
• 期刊: MedComm
• 影响因子: 9.9
• 作者: Ward AB;Keeton AB;Chen X;Mattox TE;Coley AB;Maxuitenko YY;Buchsbaum DJ;Randall TD;Zhou G;Piazza GA
• 通讯作者: Piazza GA