The Role of IL-15 in Cutaneous T-cell Lymphoma Progression

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PROJECT SUMMARY Cutaneous T-cell Lymphoma (CTCL) is an incurable disease characterized by the localization of neoplastic T lymphocytes to the skin. Patients display a progressive disease pattern, limited to the skin, often requiring life- long treatment, significantly impacting the quality of life. Given that the incidence of CTCL is rising and long-term treatments are needed to manage the debilitating skin lesions caused by this disease, there is an urgent need to better understand the mechanisms of neoplastic T-cell localization to the skin and disease progression. Given our new findings highlighting the role of tumor-derived interleukin-15 (IL-15) signaling in CTCL progression in the skin, this pathway presents an opportunity to understand the role of inflammatory cytokines in the skin- tropism of CTCL. Using a transgenic mouse model of IL-15, we previously showed that IL-15 overexpression induces a spontaneous CTCL that phenotypically mimics human CTCL. IL-15 transgenic mice show an early accumulation of neoplastic T-cells and persistent keratinocyte hyperplasia, resulting in immune cell recruitment and skin inflammation. IL-15 is also chronically elevated in CTCL patients, and neoplastic T-cells derived factors are suggested to cause skin inflammation. We have discovered a new signaling cascade in which IL-15 induces constitutive activation of skin-homing chemokine receptors on the malignant T-cells, thereby promoting their ligand-dependent localization to the skin in CTCL. Pharmacological inhibition of IL-15 blocks this signaling pathway, thereby preventing cell migration and keratinocyte proliferation. To fully establish this pathway and its role in CTCL progression, we will - 1) elucidate mechanisms of IL-15 production in CTCL, 2) evaluate the impact of IL-15 on lymphoma cell migration to the skin, 3) clarify the IL-15 dependent mechanisms of CTCL progression in the skin, 4) understand how this leads to chronic skin inflammation, and 5) evaluate therapeutic potential of blocking IL-15 pathway in CTCL treatment. The proposed studies will expand our fundamental understanding of the mechanisms that control CTCL progression in the skin and will lay the foundation for developing novel anti- IL-15 therapies that inhibit oncogenic signaling in the treatment of CTCL.