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Reengineering Tumor Microenvironment with Sequential Interleukin Delivery

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Department of Basic Medical Sciences, Purdue University, 625 Harrison St., West Lafayette, IN 47907, USA
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Purdue Center for Cancer Research and Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA
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Department of Chemical Engineering, University of Virginia, Charlottesville, VA 22904, USA
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Université de Strasbourg, CNRS, Institut Charles Sadron UPR22, F-67000 Strasbourg, France
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Department of Polymer Science & Engineering, University of Massachusetts, 120 Governors Drive, Amherst, MA 01003, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Jarek Baran
Bioengineering 2021, 8(7), 90; https://doi.org/10.3390/bioengineering8070090
Received: 5 June 2021 / Revised: 25 June 2021 / Accepted: 27 June 2021 / Published: 30 June 2021
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. View Full-Text
Keywords: Interleukin-27; targeted IL-27pepL; Interleukin-18; prostate cancer; immune effector signatures; sonoporation; sequential delivery Interleukin-27; targeted IL-27pepL; Interleukin-18; prostate cancer; immune effector signatures; sonoporation; sequential delivery
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MDPI and ACS Style

Figueiredo, M.L.; Letteri, R.; Chan-Seng, D.; Kumar, S.; Rivera-Cruz, C.M.; Emrick, T.S. Reengineering Tumor Microenvironment with Sequential Interleukin Delivery. Bioengineering 2021, 8, 90. https://doi.org/10.3390/bioengineering8070090

AMA Style

Figueiredo ML, Letteri R, Chan-Seng D, Kumar S, Rivera-Cruz CM, Emrick TS. Reengineering Tumor Microenvironment with Sequential Interleukin Delivery. Bioengineering. 2021; 8(7):90. https://doi.org/10.3390/bioengineering8070090

Chicago/Turabian Style

Figueiredo, Marxa L., Rachel Letteri, Delphine Chan-Seng, Shreya Kumar, Cosette M. Rivera-Cruz, and Todd S. Emrick. 2021. "Reengineering Tumor Microenvironment with Sequential Interleukin Delivery" Bioengineering 8, no. 7: 90. https://doi.org/10.3390/bioengineering8070090

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