IL-15 superagonist RLI has potent immunostimulatory properties on NK cells: implications for antimetastatic treatment.
Animals
Carcinoma, Non-Small-Cell Lung
/ drug therapy
Cell Line, Tumor
/ transplantation
Female
Healthy Volunteers
Humans
Interleukin-15
/ administration & dosage
Killer Cells, Natural
/ drug effects
Lung
/ drug effects
Lung Neoplasms
/ drug therapy
Mammary Neoplasms, Experimental
/ drug therapy
Mice
Primary Cell Culture
Recombinant Fusion Proteins
/ administration & dosage
Recombinant Proteins
/ administration & dosage
Tumor Microenvironment
/ drug effects
IL-15
IL-15/IL-15Rα complex
NK cells
cancer
immunotherapy
metastasis
microenvironment
neutrophils
trans-signaling
Journal
Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
accepted:
07
04
2020
entrez:
14
6
2020
pubmed:
14
6
2020
medline:
22
5
2021
Statut:
ppublish
Résumé
As the immune system is compromised in patients with cancer, therapeutic strategies to stimulate immunity appear promising, to avoid relapse and increase long-term overall survival. Interleukin-15 (IL-15) has similar properties to IL-2, but does not cause activation-induced cell death nor activation and proliferation of regulatory T cells (Treg), which makes it a serious candidate for anticancer immunotherapy. However, IL-15 has a short half-life and high doses are needed to achieve responses. Designed to enhance its activity, receptor-linker-IL-15 (RLI) (SO-C101) is a fusion molecule of human IL-15 covalently linked to the human IL-15Rα sushi+ domain currently assessed in a phase I/Ib clinical trial on patients with advanced/metastatic solid cancer. We investigated the antimetastatic activity of RLI in a 4T1 mouse mammary carcinoma that spontaneously metastasizes and evaluated its immunomodulatory role in the metastatic lung microenvironment. We further characterized the proliferation, maturation and cytotoxic functions of natural killer (NK) cells in tumor-free mice treated with RLI. Finally, we explored the effect of RLI on human NK cells from healthy donors and patients with non-small cell lung cancer (NSCLC). RLI treatment displayed antimetastatic properties in the 4T1 mouse model. By characterizing the lung microenvironment, we observed that RLI restored the balance between NK cells and neutrophils (CD11b Collectively, our work demonstrates superior activity of RLI compared with rhIL-15 in modulating and activating NK cells and provides additional evidences for a therapeutic strategy using RLI as antimetastatic molecule.
Sections du résumé
BACKGROUND
As the immune system is compromised in patients with cancer, therapeutic strategies to stimulate immunity appear promising, to avoid relapse and increase long-term overall survival. Interleukin-15 (IL-15) has similar properties to IL-2, but does not cause activation-induced cell death nor activation and proliferation of regulatory T cells (Treg), which makes it a serious candidate for anticancer immunotherapy. However, IL-15 has a short half-life and high doses are needed to achieve responses. Designed to enhance its activity, receptor-linker-IL-15 (RLI) (SO-C101) is a fusion molecule of human IL-15 covalently linked to the human IL-15Rα sushi+ domain currently assessed in a phase I/Ib clinical trial on patients with advanced/metastatic solid cancer.
METHODS
We investigated the antimetastatic activity of RLI in a 4T1 mouse mammary carcinoma that spontaneously metastasizes and evaluated its immunomodulatory role in the metastatic lung microenvironment. We further characterized the proliferation, maturation and cytotoxic functions of natural killer (NK) cells in tumor-free mice treated with RLI. Finally, we explored the effect of RLI on human NK cells from healthy donors and patients with non-small cell lung cancer (NSCLC).
RESULTS
RLI treatment displayed antimetastatic properties in the 4T1 mouse model. By characterizing the lung microenvironment, we observed that RLI restored the balance between NK cells and neutrophils (CD11b
CONCLUSIONS
Collectively, our work demonstrates superior activity of RLI compared with rhIL-15 in modulating and activating NK cells and provides additional evidences for a therapeutic strategy using RLI as antimetastatic molecule.
Identifiants
pubmed: 32532840
pii: jitc-2020-000632
doi: 10.1136/jitc-2020-000632
pmc: PMC7295443
pii:
doi:
Substances chimiques
IL-15Ralpha-sushi domain-linker-IL-15 fusion protein
0
IL15 protein, human
0
Interleukin-15
0
Recombinant Fusion Proteins
0
Recombinant Proteins
0
Types de publication
Comparative Study
Journal Article
Observational Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: MD, DB and NC disclose a potential conflict of interest. MD received income from Cytune Pharma SAS. DB is director and shareholder of Cytune Pharma SAS. NC received grant supports from Cytune Pharma.
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