Reengineering Tumor Microenvironment with Sequential Interleukin Delivery
Open Access
- 30 June 2021
- journal article
- research article
- Published by MDPI AG in Bioengineering
- Vol. 8 (7), 90
- https://doi.org/10.3390/bioengineering8070090
Abstract
Some cytokines can reengineer anti-tumor immunity to modify the tumor micro-environment. Interleukin-27 (IL-27) can partially reduce tumor growth in several animal models, including prostate cancer. We hypothesized that addition of IL-18, which can induce the proliferation of several immune effector cells through inducing IFNγ could synergize with IL-27 to enhance tumor growth control. We describe our findings on the effects of IL-27 gene delivery on prostate cancer cells and how sequential therapy with IL-18 enhanced the efficacy of IL-27. The combination of IL-27 followed by IL-18 (27→18) successfully reduced cancer cell viability, with significant effects in cell culture and in an immunocompetent mouse model. We also examined a novel chimeric cytokine, comprising an IL-27 targeted at the C-terminus with a short peptide, LSLITRL (27pepL). This novel cytokine targets a receptor upregulated in tumor cells (IL-6Rα) via the pepL ligand. Interestingly, when we compared the 27→18 combination with the single 27pepL therapy, we observed a similar efficacy for both. This efficacy was further enhanced when 27pepL was sequenced with IL-18 (27pepL→18). The observed reduction in tumor growth and significantly enriched canonical pathways and upstream regulators, as well as specific immune effector signatures (as determined by bioinformatics analyses in the tumor microenvironment) supported the therapeutic design, whereby IL-27 or 27pepL can be more effective when delivered with IL-18. This cytokine sequencing approach allows flexible incorporation of both gene delivery and recombinant cytokines as tools to augment IL-27’s bioactivity and reengineer efficacy against prostate tumors and may prove applicable in other therapeutic settings.Funding Information
- National Institutes of Health (R01CA196947, R01AR069079)
This publication has 49 references indexed in Scilit:
- Ligand-Mediated Targeting of Cytokine Interleukin-27 Enhances Its Bioactivity In VivoMolecular Therapy - Methods & Clinical Development, 2020
- IL‐27 stimulates human NK‐cell effector functions and primes NK cells for IL‐18 responsivenessEuropean Journal of Immunology, 2014
- Polymer–Peptide Delivery Platforms: Effect of Oligopeptide Orientation on Polymer-Based DNA DeliveryBiomacromolecules, 2014
- Interleukin-27 Gene Delivery for Modifying Malignant Interactions Between Prostate Tumor and BoneHuman Gene Therapy, 2013
- Sonoporation Delivery of Interleukin-27 Gene Therapy Efficiently Reduces Prostate Tumor Cell Growth In VivoHuman Gene Therapy, 2011
- IL-18 Inhibits Growth of Murine Orthotopic Prostate Carcinomas via Both Adaptive and Innate Immune MechanismsPLOS ONE, 2011
- IL-12 and IL-27 Sequential Gene Therapy via Intramuscular Electroporation Delivery for Eliminating Distal Aggressive TumorsThe Journal of Immunology, 2010
- Interleukin-23 and Interleukin-27 Exert Quite Different Antitumor and Vaccine Effects on Poorly Immunogenic MelanomaCancer Research, 2006
- Cutting Edge: Role of IL-27/WSX-1 Signaling for Induction of T-Bet Through Activation of STAT1 During Initial Th1 CommitmentThe Journal of Immunology, 2003
- Interleukin‐18 acts as an angiogenesis and tumor suppressorThe FASEB Journal, 1999