This MMHC consortium proposal will address the immunobiology of carcinogenesis, in particular three critical issues related to mechanisms by which organ specific cancers develop, and to strategies aimed at treating or preventing cancer, as revealed by and to be studied in several genetically engineered mouse models of human cancer. The goals of the consortium team center upon: i) elucidating the cell and molecular mechanisms of immune enhancement, whereby cells of the innate and acquired immune system are recruited to infiltrate neoplastic lesions, wherein they have been shown to be capable of functionally enhancing neoplastic progression, in part by activating angiogenesis and amplifying tumor cell growth; ii) identifying the molecular basis of implicit barriers to T cell inflammation and killing of solid tumors that are evident in certain mouse models and further assessing its generality, and iii) refining strategies for induction of efficacious T cell immunotherapies in fully immunocompetent models of organ-specific carcinogenesis, both assessing and seeking to circumvent the potential interference with efficacy by immune enhancement and inflammatory barriers. The consortium team will investigate the regulation and manifestation of these interrelated facets of tumor immunobiology in a select group of organ-specific cancers, of breast, cervix, and pancreatic islet. The group will ask whether immune enhancement and inflammatory barriers are factors for premalignant and nascent tumor stages of carcinogenesis in these organs, and/or for the continuing growth and progression of well established solid tumors. The experimental designs will reveal whether immune enhancement and inflammatory barriers vary as a function of organ site and stage of progression, and provide insight into the possibility that these parameters can impact upon the success of tumor immunotherapy. The prospects for improving the efficacy of T cell immunity against either premalignant or malignant lesions in breast, cervix, and pancreas by combining mechanism-based disruptions in immune enhancement or inflammatory barriers will be assessed in preclinical trials. A remarkable group of tumor biologists and immunologists has been assembled to pursue these strategic goals with their collectively enabling and complementary expertise.
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