Role of microbiota in therapy to ovarian cancer

该提案是为了回应 RFA“NCI 的挑衅性问题的研究答案”而提交的。 特别是问题 10，该问题询问：微生物群如何影响对癌症治疗的反应？我们的 初步数据表明，当肿瘤细胞定植于大网膜（腹膜腔中的脂肪组织）时，它们 触发深远的 Treg 介导的耐受性反应，阻止肿瘤特异性 CD8 T 细胞的清除 肿瘤。有趣的是，这种活动是大网膜特有的，涉及 Tregs 的一个子集，称为 内脏脂肪组织 (VAT) 相关的 Tregs。 VAT相关Tregs独特地表达转录 PPARg 因子，还在其表面表达 IL-33 受体的 ST2 成分。这些细胞是 仅在脂肪组织中发现，在传统的淋巴器官（如脾脏和淋巴器官）中不存在 淋巴结）并且在外周部位未发现。重要的是，与增值税相关的 Tregs 存在于 大网膜，这是卵巢癌转移的部位。除了表明与增值税相关的 Tregs 严重损害对定植于大网膜的肿瘤的免疫力，我们还发现这种活性完全是 取决于肠道微生物群。结果，VAT 相关 Treg 活性受损，抗肿瘤免疫功能受损 在无菌小鼠的网膜中恢复。这些结果令人惊讶，因为公布的数据表明 微生物群促进（而不是阻止）化疗的抗肿瘤作用。这些结果得到了解释 通过化疗损害肠道上皮的能力，允许微生物群的易位和 从而触发IL-17反应，促进化疗对肿瘤清除的作用。 基于这些数据，该提案的中心假设是微生物群在 在稳态条件下促进免疫抑制性Tregs，并通过促进免疫 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 VAT 相关的 Tregs 主要存在于大网膜等脂肪组织中并对其作出反应。 因此，对通常转移至大网膜的卵巢癌的治疗可能会产生不同的结果 比治疗其他部位的肿瘤更有效。本应用中的实验使用 卵巢癌自发小鼠模型并确定肠道微生物群之间的机制联系 和腹腔免疫使用和卵巢癌异位模型。

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.