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Heterodimeric IL-15 (hetIL-15) reduces circulating tumor cells and metastasis formation improving chemotherapy and surgery in 4T1 mouse model of TNBC

  1. Author:
    Stravokefalou, Vasiliki
    Stellas, Dimitris
    Karaliota,Sevasti
    Nagy,Bethany
    Valentin, Antonio
    Bergamaschi, Cristina
    Dimas, Konstantinos
    Pavlakis,George

  2. Author Address

    Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, United States., Department of Pharmacology, Faculty of Medicine, University of Thessaly, Larissa, Greece., Department of Chemical Biology, National Hellenic Research Foundation, Athens, Greece., Basic Science Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, MD, United States., Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, MD, United States., Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, United States.,
    1. Year: 2022
    2. Date: Jan 13
    3. Epub Date: 2023 01 13
  2. Journal: Frontiers in Immunology
    1. 13
    2. Pages: 1014802
  4. Type of Article: Article
  5. Article Number: 1014802
  1. Abstract:

    Immunotherapy has emerged as a viable approach in cancer therapy, with cytokines being of great interest. Interleukin IL-15 (IL-15), a cytokine that supports cytotoxic immune cells, has been successfully tested as an anti-cancer and anti-metastatic agent, but combinations with conventional chemotherapy and surgery protocols have not been extensively studied. We have produced heterodimeric IL-15 (hetIL-15), which has shown anti-tumor efficacy in several murine cancer models and is being evaluated in clinical trials for metastatic cancers. In this study, we examined the therapeutic effects of hetIL-15 in combination with chemotherapy and surgery in the 4T1 mouse model of metastatic triple negative breast cancer (TNBC). hetIL-15 monotherapy exhibited potent anti-metastatic effects by diminishing the number of circulating tumor cells (CTCs) and by controlling tumor cells colonization of the lungs. hetIL-15 treatment in combination with doxorubicin resulted in enhanced anti-metastatic activity and extended animal survival. Systemic immune phenotype analysis showed that the chemoimmunotherapeutic regimen shifted the tumor-induced imbalance of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in favor of cytotoxic effector cells, by simultaneously decreasing PMN-MDSCs and increasing the frequency and activation of effector (CD8+T and NK) cells. Tumor resection supported by neoadjuvant and adjuvant administration of hetIL-15, either alone or in combination with doxorubicin, resulted in the cure of approximately half of the treated animals and the development of anti-4T1 tumor immunity. Our findings demonstrate a significant anti-metastatic potential of hetIL-15 in combination with chemotherapy and surgery and suggest exploring the use of this regimen for the treatment of TNBC. Copyright © 2023 Stravokefalou, Stellas, Karaliota, Nagy, Valentin, Bergamaschi, Dimas and Pavlakis.

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External Sources

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  2. DOI: 10.3389/fimmu.2022.1014802
  3. PMID: 36713398
  4. PMCID: PMC9880212

Library Notes

  1. Fiscal Year: FY2022-2023
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