Host STING pathway in anti-tumor immunity

描述（由申请人提供）：尽管表达了许多抗原，但大多数癌症进行性生长并逃避免疫。最近的证据表明有两大类免疫逃逸-一个主要的肿瘤亚群缺乏基于T细胞的炎症证据，可能代表免疫学无知的情况;但第二个亚群确实含有活化的CD 8 + T细胞，这些细胞似乎通过免疫抑制途径被抑制。第二个子集似乎包括大多数对临床上目前研究的免疫疗法有反应的患者，这使得理解在患者子集中驱动这种自发阴燃抗肿瘤免疫应答的机制成为一个主要的基本问题。从人类黑色素瘤样本的基因表达谱开始，并通过小鼠的机制研究，我们最近发现了宿主I型IFN产生的关键作用，作为先天免疫传感和自发CD 8 + T细胞引发之间的桥梁，以应对体内肿瘤的生长。但是，是什么宿主先天免疫途径检测肿瘤产物并驱动I型IFN的产生呢？出乎意料的是，我们的初步数据表明，它是肿瘤衍生的DNA激活了一条涉及衔接子STING的途径，以驱动APC产生IFN-γ。在STING-/-小鼠中，由肿瘤引起的自发T细胞引发被消融，并且通常自发排斥的免疫原性肿瘤进行性生长。该提案的总体目标是了解宿主STING途径在体内被肿瘤激活的机制，并确定非炎症人类黑色素瘤中该途径的阻断水平。在第一个具体目标中，我们将研究DNA转移到宿主APC以驱动IFN-γ产生以响应体内肿瘤挑战的机制。将使用多种方法来追踪肿瘤来源的DNA转移，并对接受DNA并响应IFN-γ产生的APC进行表型分析。宿主DNA酶II在限制这种反应中的作用将被确定。一种新的可诱导遗传黑色素瘤模型将用于补充可移植肿瘤的数据。在第二个具体目标中，将评估候选DNA传感器和调节剂对宿主STING途径的调节。重点将放在cGAS，p204和AIM 2上。将在体外研究通过STING途径对信号传导的影响，并将使用基因靶向小鼠在体内询问抗肿瘤免疫。在第三个具体目标中，将评价已经表征了CD 8 + T细胞浸润水平的人黑素瘤样品在该肿瘤DNA传感途径中的阻断水平，以解读主要患者亚群中自发免疫识别失败的原因。总之，这些结果将阐明参与宿主识别肿瘤的新的基本过程，并且将使得能够设计新的策略来促进体内有效的抗肿瘤免疫，特别是在缺乏自发宿主免疫应答的情况下。

DESCRIPTION (provided by applicant): Most cancers grow progressively and evade immunity, despite expression of numerous antigens. Recent evidence has suggested two broad categories of immune escape - a major subset of tumors lacks evidence for T cell-based inflammation and likely represents a situation of immunologic ignorance; but a second subset does indeed contain activated CD8+ T cells that seem to be suppressed through immune inhibitory pathways. The second subset appears to include the majority of patients who respond to currently studied immunotherapies in the clinic, which makes understanding the mechanism driving this spontaneous smoldering anti-tumor immune response in a subset of patients a major fundamental question. Beginning with gene expression profiling of human melanoma samples and through mechanistic studies in mice, we recently have uncovered a critical role for host type I IFN production as a bridge between innate immune sensing and spontaneous CD8+ T cell priming in response to a growing tumor in vivo. But what host innate immune pathway detects a tumor product and drives type I IFN production? Unexpectedly, our preliminary data have suggested that it is tumor-derived DNA which activates a pathway involving the adapter STING to drive IFN-¿ production by APCs. In STING-/- mice, spontaneous T cell priming by tumors is ablated, and immunogenic tumors that normally are spontaneously rejected grow progressively. The overall goal of this proposal is to understand the mechanism by which the host STING pathway becomes activated by tumors in vivo, and to identify the level of block in this pathway in non-inflamed human melanomas. In the first specific aim, we will investigate the mechanisms by which DNA becomes transferred to host APCs to drive IFN-¿ production in response to tumor challenge in vivo. Multiple methods will be used to track tumor derived DNA transfer and to phenotype the APCs taking up DNA and responding with IFN-¿ production. The role for host DNase II in limiting this response will be determined. A novel inducible genetic melanoma model will be used to supplement data with transplantable tumors. In the second specific aim, the regulation of the host STING pathway by candidate DNA sensors and regulators will be evaluated. The focus will be on cGAS, p204, and AIM2. Impact on signaling through the STING pathway will be studied in vitro, and anti-tumor immunity will be interrogated in vivo using gene-targeted mice. In the third specific aim, human melanoma samples already characterized for the level of CD8+ T cell infiltration will be evaluated for the level of block inthis tumor DNA sensing pathway to decipher the reason for failed spontaneous immune recognition in a major subset of patients. Together, these results will elucidate a new fundamental process involved in the host recognition of tumors, and will enable the design of new strategies to promote effective anti-tumor immunity in vivo, particularly in cases that lack spontaneous host immune responses.