Role of microbiota in therapy to ovarian cancer

本提案是对RFA的回应，《对NCI的挑衅性问题的研究解答》，载于 特别是问题10，它问的是微生物区系如何影响对癌症治疗的反应？我们的 初步数据显示，当肿瘤细胞定居在腹膜--腹膜中的一种脂肪组织--时，它们 触发深刻的Treg介导的耐受反应，阻止肿瘤特异性CD8 T细胞清除 肿瘤。有趣的是，这一活动是特定于大网膜的，并且涉及到称为 内脏脂肪组织(VAT)相关树。VAT相关的Tregs唯一表达转录 因子PPARg，并表达其表面IL-33受体的ST2成分。这些细胞是 仅在脂肪组织中发现，而在常规淋巴器官(如脾和 淋巴结节)，在外周部位未发现。重要的是，与增值税相关的树可以在 大网膜，这是卵巢癌转移的地方。除了显示增值税相关树之外 我们还发现，这种活性完全是 依赖肠道微生物区系。其结果是，增值税相关的Treg活性受损，抗肿瘤免疫受到影响 在无菌小鼠的大网膜中恢复。这些结果令人惊讶，因为公布的数据显示 微生物区系促进(而不是阻止)化疗的抗肿瘤效果。对这些结果进行了解释 通过化疗损害肠道上皮的能力，允许微生物区系和 从而触发IL-17反应，从而促进化疗对肿瘤清除的影响。 基于这些数据，这一提议的中心假设是微生物区系在 促进稳定状态下的免疫抑制树和通过促进免疫 化疗后的刺激性Th17反应。此外，这些类型的响应是位置 依赖，与增值税相关的Tregs主要驻留和反应在大网膜等脂肪组织中。 因此，卵巢癌的治疗可能会有不同的结果，卵巢癌通常会转移到大网膜。 而不是治疗其他地方的肿瘤。此应用程序中的实验使用 自发建立小鼠卵巢癌模型并确定肠道微生物区系之间的机制联系 并采用异位卵巢癌模型和腹腔免疫。

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.