We seek to continue the productive interactions of Project 5 in P01 CA100730 by examining the role of innate and adaptive immunity in the initiation and maintenance of HTLV-1 Tax-mediated lymphoma. A variety of animal models and clinical reports support the role of inflammatory mediators in the promotion of cancer, yet the molecular links between inflammation and cancer are incompletely understood. Inflammatory mediators and viral factors that promote cell proliferation are intimately linked in HTLV-1-induced carcinogenesis and have been a long-term interest of Dr. Ratner (Project 5). The PPG investigators have extensively collaborated using molecular clones and animal models to provide fundamental information about the pathogenesis of the viral infection and mechanisms of ATL including the development of novel transgenic mouse models that have demonstrated the role of NFicB in cancer development. In the proposed Project 5, we will extend his model to test the role of inflammation in novel T cell lymphoma models. Adult T cell leukemia / lymphoma (ATL), caused by HTLV-1, is an aggressive T cell malignancy driven primarily by NFxB signaling pathways. The model systems chosen are transgenic mouse models of HTLV-1 Tax, which results in the development of lymphoma in a microenvironment of inflammatory cells. The role of neutrophils in the innate immune system will be examined in Aim 2 using myeloperoxidase knockout mice. The role of T cells in the adaptive immune system will be examined in Aims 1 and 3, using T cell receptor activation or mitogen and/or miRNA (HBZ) induction of T cell proliferation.
The Specific Aims of the Project are: 1) Test T Cell activation in Tax tumorigenesis by utilizing T-cell receptor (TCR) transgenic and Tax transgenic mice to examine the contributions of innate and adaptive immunity to initiation and maintenance of tumors, 2) Test neutrophil activation in Tax-mediated tumorigenesis by examining neutrophil activation in inflammatory lesions and tumors in myeloperoxidase knockout mice, and 3) Determine the combined Influence of T cell activation and inflammation by examining the role of a novel anti-sense encoded viral miRNA (HBZ) that activates T-cells and contributes to HTLV-1-mediated tumorigenesis. These highly collaborative studies will provide new insights into molecular and cellular pathways that are critical to a wide variety of malignancies and offer insight into beneficial intervention strategies against cancer.
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