Role of microbiota in therapy to ovarian cancer

该提案是为了回应RFA，“研究回答NCI的挑衅性问题”， 特别是问题10，它问，微生物群如何影响对癌症治疗的反应？我们 初步数据显示，当肿瘤细胞定植于网膜（腹膜腔中的脂肪组织）时， 触发深刻的Treg介导的耐受性反应，阻止肿瘤特异性CD 8 T细胞清除 肿瘤有趣的是，这种活动对网膜是特异性的，并且涉及一种称为 内脏脂肪组织（VAT）相关性甲状腺炎。VAT相关的T细胞独特地表达转录 因子PPARg，并且还在其表面上表达IL-33受体的ST 2组分。这些细胞 仅存在于脂肪组织中，而不存在于常规的类肉瘤器官（如脾和 淋巴结）中，并且在外周部位中未发现。重要的是，VAT相关的T细胞存在于 网膜，这是卵巢癌转移的部位。除了显示与VAT相关的T细胞 我们还发现，这种活性完全抑制了对定植在网膜上的肿瘤的免疫力， 依赖于肠道菌群结果，VAT相关Treg活性受损，抗肿瘤免疫被抑制。 在无菌小鼠的网膜中恢复。这些结果令人惊讶，因为公布的数据显示， 微生物群促进（而不是阻止）化疗的抗肿瘤作用。对这些结果进行了解释 化疗能够损害肠道上皮，使微生物群移位， 从而触发IL-17应答，这促进了化疗对肿瘤清除的作用。 基于这些数据，该提议的中心假设是，微生物群在体内发挥相反的作用。 在稳态条件下促进免疫抑制性T细胞活化，并通过促进免疫抑制性T细胞活化， 化疗后刺激性Th 17应答。此外，这些类型的响应是位置 依赖性的，与VAT相关的T细胞主要在脂肪组织如网膜中驻留和响应。 因此，卵巢癌通常转移到网膜，治疗可能有不同的结果 比治疗其他部位的肿瘤更有效。本申请中的实验使用 自发性卵巢癌小鼠模型，并确定肠道微生物群之间的机制联系 腹腔免疫功能测定。

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.