Inflammation and immunity in the crucible of premalignancy

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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, γδ, 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-1ß 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.