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

Award Number: R01CA266592
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/20/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $356,850 )
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	000	3	6/27/2025	NON-COMPETING CONTINUATION	$356,850
														Subtotal = $356,850

Issue Date FY: 2024 ( Subtotal = $339,008 )
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	000	2	7/15/2024	NON-COMPETING CONTINUATION	$339,008
														Subtotal = $339,008

Issue Date FY: 2023 ( Subtotal = $356,850 )
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	000	1	7/20/2023	NEW	$356,850
														Subtotal = $356,850

Grand Total All Awards = $1,052,708

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

Award Number: R01CA266592

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/20/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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