Inflammation and immunity in the crucible of premalignancy

描述(由申请人提供)：炎症和细胞免疫可能在肿瘤发展的癌前阶段对多步癌变有最大的影响。炎症和免疫在癌前阶段也有望参与广泛的交叉调节，但由于缺乏易于处理的模型系统，影响肿瘤进展和发病率的关键相互作用在很大程度上仍未确定。这项建议将描述最近建立的I型子宫内膜癌(EC)Ptenlox/lox PRcre/(P10/PR-cre)小鼠模型在癌前阶段的交叉调节免疫回路。该模型涉及子宫组成性缺失Pten抑癌基因，其关键特征是肿瘤形成迅速、完全穿透和在整个子宫内同步，4周龄的增生性病变到3个月龄的侵袭性癌进展顺利。此外，P10/PR-cre小鼠的增生性病变虽然是癌前病变，但与上皮内多形核中性粒细胞(PMN)大量聚集、NK、β、CD8和CD4T细胞密度升高以及混合Th1/Th17细胞免疫反应有关。由于子宫是一个相对较大但非必要的器官，可以对留置免疫细胞行为进行详细分析，因此该模型提供了一个前所未有的机会，可以机械地剖析癌前病变期间的调节途径。目的I是基于初步数据显示，在4周龄时出现的急性子宫炎症是在相对免疫静止状态之前的，并将表征似乎是启动全面炎症的离散触发因素，潜在地由树突状细胞(DC)和先天淋巴样细胞之间的协作驱动。AIM II是基于初步数据显示癌前子宫处于DC免疫密切监视下，并将确定PMN及其分泌产物PGE2和IL-1如何？调节肿瘤相关树突状细胞，最终控制癌前相关细胞免疫反应的大小和极性。最后，Aim III将确定IL-17依赖和非依赖途径在P10/PR-cre小鼠子宫炎症和肿瘤进展中的作用。总之，这项工作将建立P10/PR-cre小鼠作为一种新的、强大的动物模型来从机械上探索癌前肿瘤微环境，这里提出的具有景观定义的实验可能揭示与多种上皮性癌症的发展相关的宿主-肿瘤相互作用的特征。

DESCRIPTION (provided by applicant): Inflammation and cellular immunity likely have their greatest influence over multistep carcinogenesis during the premalignant stage of tumor development. Inflammation and immunity are also expected to engage in extensive cross-regulation during premalignancy, but the key interactions that will influence tumor progression and incidence remain largely undefined due to the lack of tractable model systems. This proposal will characterize the cross-regulatory immune circuitry operative during premalignancy in the recently established Ptenlox/lox PRcre/+ (P10/PR-cre) mouse model of type I endometrial carcinoma (EC). This model involves constitutive uterine deletion of the Pten tumor suppressor gene, and has the key features that tumor formation is rapid, completely penetrant, and synchronous throughout the uterus, with hyperplasia at 4 wks of age unfailingly progressing to invasive carcinoma by 3 months of age. Moreover, the hyperplastic lesions of P10/PR-cre mice, while premalignant, are associated with massive accumulations of intraepithelial polymorphonuclear neutrophils (PMNs), elevated densities of NK, ??, CD8, and CD4 T cells, and a mixed Th1/Th17 cellular immune response. Since the uterus is a relatively large but non-essential organ amenable to detailed analyses of indwelling immune cell behavior, this model offers an unprecedented opportunity to mechanistically dissect regulatory pathways during premalignancy. Aim I is based upon preliminary data showing that the acute uterine inflammation apparent at 4 wks of age is preceded by a state of relative immunological quiescence, and will characterize what appears to be a discrete trigger that initiates full-blown inflammation, potentially driven by a collaboration between dendritic cells (DCs) and innate lymphoid cells. Aim II is based upon preliminary data showing that premalignant uteri are under close DC immunosurveillance, and will determine how PMNs and their secreted products PGE2 and IL-1? regulate tumor-associated DCs to ultimately control the magnitude and polarity of the premalignancy-associated cellular immune response. Lastly, Aim III will determine the contributions of IL-17-dependent and -independent pathways to uterine inflammation and tumor progression in P10/PR-cre mice. Together, this work will establish P10/PR-cre mice as a new and powerful animal model to mechanistically probe the premalignant tumor microenvironment, with the landscape-defining experiments proposed here likely to reveal features of host-tumor interactions relevant to the development of many kinds of epithelial cancers.