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

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2024 · $339,008

## Abstract

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.

## Key facts

- **NIH application ID:** 10891650
- **Project number:** 5R01CA266592-02
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Anjali Mishra
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $339,008
- **Award type:** 5
- **Project period:** 2023-07-20 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891650

## Citation

> US National Institutes of Health, RePORTER application 10891650, The Role of IL-15 in Cutaneous T-cell Lymphoma Progression (5R01CA266592-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10891650. Licensed CC0.

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