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Review
. 2023 Apr 20:14:1141208.
doi: 10.3389/fimmu.2023.1141208. eCollection 2023.

The role of interleukin-15 in the development and treatment of hematological malignancies

Paola Sindaco  1   2 , Hritisha Pandey  1 , Colleen Isabelle  1 , Nitin Chakravarti  1   2 , Jonathan Edward Brammer  3 , Pierluigi Porcu  1   2 , Anjali Mishra  1   2   4
Affiliations
Review

The role of interleukin-15 in the development and treatment of hematological malignancies

Paola Sindaco et al. Front Immunol. .

Abstract

Cytokines are a vital component of the immune system that controls the activation and growth of blood cells. However, chronic overexpression of cytokines can trigger cellular events leading to malignant transformation. The cytokine interleukin-15 (IL-15) is of particular interest, which has been shown to contribute to the development and progression of various hematological malignancies. This review will provide an overview of the impact of the immunopathogenic function of IL-15 by studying its role in cell survival, proliferation, inflammation, and treatment resistance. We will also review therapeutic approaches for inhibiting IL-15 in blood cancers.

Keywords: IL-15; blood; cancer; cytokine; treatment.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Therapeutic approaches on Interleukin-15 signaling. IL-15 signaling. Interleukin-15 (IL-15) plays a major role in the immune responses by serving as a growth factor for T- and NK-cells. Normal IL-15 signaling begins following the binding of IL-15, produced by dendritic cells, with its high affinity receptor IL-15Rα on the same cells (cis presentation). Upon binding, it is trans-presented to the IL-2R/15Rβ-γc receptor complex expressed by T- and NK-cells, which consequently activates JAK1/JAK3 along with STAT3/5, PI3K/Akt and Ras/Raf/MAPK. These signaling cascades trigger a transcriptional program aimed at boosting the anti-pathogens inflammatory response and enhancing the anti-tumoral immune response. Paradoxically, the overexpression of IL-15 can result in the development of hematological malignancies. IL-15 inhibiting therapies. Numerous interventions have been developed to block IL-15 signaling and the T- and NK-cells tumoral proliferation. Some examples are anti-IL-15 antibody (Hu-Mikβ1, 04H04, TM-β1, anti-CD-132), peptide antagonists (BNZ-1, BNZ132-1), and fusion proteins (soluble IL-15Rα-sIL15Rα, IL-15 mutant/Fcγ2a, H9-RETR IL-2 mutein). IL-15 enhancing therapies. Highly efficient immune response enhancing agents have been developed to leverage the ability of IL-15 to boost the anti-tumoral effector cells. The figure depicts recombinant agonists (sch rhIL-15, NKTR-255, NIZ985), fusion proteins (receptor linker IL-15 or RLI, ALT-803, hetIL-15FC), and unique delivery systems (RTX-240, CLPP/mIL-15, MS~IL-15). These compounds boost the immune response against tumoral cells and can potentiate the effect of immunotherapy and adoptive cell therapy. Figure made with Biorender.com.
See this image and copyright information in PMC

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