Abstract
IL-15 is a promising cytokine to expand NK and CD8+ T cells for cancer immunotherapy, but its application is limited by dose-limiting, on-target off-tumor toxicity. Here, we have developed a next-generation IL-15 that is activated inside the tumor microenvironment (TME). This pro-IL-15 has the extracellular domain of IL-15Rβ fused to the N-terminus of sIL-15-Fc through a tumor-enriched Matrix Metalloproteinase (MMP) cleavable peptide linker to block its activity. Unlike sIL-15-Fc, pro-IL-15 does not activate the peripheral expansion of NK cells and T cells, thus reducing systemic toxicity, but it still preserves efficient anti-tumor abilities. In various mouse tumors, the anti-tumor effect of pro-IL-15 depends on intratumoral CD8+ T cells and IFN-γ. Pro-IL-15 increases the stem-like TCF1+Tim-3−CD8+ T cells within tumor tissue and helps overcome immune checkpoint blockade (ICB) resistance. Moreover, pro-IL-15 synergizes with current tyrosine kinase inhibitor (TKI) targeted-therapy in a poorly inflamed TUBO tumor model, suggesting that pro-IL-15 helps overcome targeted-therapy resistance. Our results demonstrate a next-generation IL-15 cytokine that can stimulate potent anti-tumor activity without severe toxicity.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Rosenberg, S. A. IL-2: the first effective immunotherapy for human cancer. J. Immunol. 192, 5451–5458 (2014).
Kolitz, J. E. et al. Recombinant interleukin-2 in patients aged younger than 60 years with acute myeloid leukemia in first complete remission: results from Cancer and Leukemia Group B 19808. Cancer 120, 1010–1017 (2014).
Sim, G. C. et al. IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients. J. Clin. Invest. 124, 99–110 (2014).
Fiore, P. F. et al. Interleukin-15 and cancer: some solved and many unsolved questions. J. Immunother. Cancer 8, e001428 (2020).
Waldmann, T. A., Dubois, S., Miljkovic, M. D. & Conlon, K. C. IL-15 in the combination immunotherapy of cancer. Front Immunol. 11, 868 (2020).
Guo, Y. et al. IL-15 superagonist-mediated immunotoxicity: role of NK cells and IFN-gamma. J. Immunol. 195, 2353–2364 (2015).
Santana Carrero, R. M. et al. IL-15 is a component of the inflammatory milieu in the tumor microenvironment promoting antitumor responses. Proc. Natl. Acad. Sci. USA 116, 599–608 (2019).
Mlecnik, B. et al. Functional network pipeline reveals genetic determinants associated with in situ lymphocyte proliferation and survival of cancer patients. Sci. Transl. Med. 6, 228ra237 (2014).
Rhode, P. R. et al. Comparison of the superagonist complex, ALT-803, to IL15 as cancer immunotherapeutics in animal models. Cancer Immunol. Res. 4, 49–60 (2016).
Chertova, E. et al. Characterization and favorablein vivoproperties of heterodimeric soluble IL-15·IL-15Rα cytokine compared to IL-15 monomer. J. Biol. Chem. 288, 18093–18103 (2013).
Mortier, E. et al. Soluble interleukin-15 receptor α (IL-15Rα)-sushi as a selective and potent agonist of IL-15 action through IL-15Rβ/γ. J. Biol. Chem. 281, 1612–1619 (2006).
McGowan, P. M. & Duffy, M. J. Matrix metalloproteinase expression and outcome in patients with breast cancer: analysis of a published database. Ann. Oncol. 19, 1566–1572 (2008).
Turunen, S. P., Tatti-Bugaeva, O. & Lehti, K. Membrane-type matrix metalloproteases as diverse effectors of cancer progression. Bioch. Biophys. Acta Mol. Cell Res. 1864, 1974–1988 (2017).
Utzschneider, D. T. et al. T cell factor 1-expressing memory-like CD8+ T cells sustain the immune response to chronic viral infections. Immunity 45, 415–427 (2016).
Im, S. J. et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537, 417–421 (2016).
He, R. et al. Follicular CXCR5-expressing CD8+ T cells curtail chronic viral infection. Nature 537, 412–416 (2016).
Ohashi, K., Maruvka, Y. E., Michor, F. & Pao, W. Epidermal growth factor receptor tyrosine kinase inhibitor–resistant disease. J. Clin. Oncol. 31, 1070–1080 (2013).
Sun, Z. et al. A next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8+ T-cell response and effective tumor control. Nat. Commun. 10, 3874 (2019).
Liu, B. et al. Evaluation of the biological activities of the IL-15 superagonist complex, ALT-803, following intravenous versus subcutaneous administration in murine models. Cytokine 107, 105–112 (2018).
Guo, Y. et al. IL-15 superagonist–mediated immunotoxicity: role of NK cells and IFN-γ. J. Immunol. 195, 2353–2364 (2015).
Yang, X. et al. Targeting the tumor microenvironment with interferon-β bridges innate and adaptive immune responses. Cancer Cell 25, 37–48 (2014).
Liang, Y. et al. Targeting IFNα to tumor by anti-PD-L1 creates feedforward antitumor responses to overcome checkpoint blockade resistance. Nat. Commun. 9, 4586 (2018).
Weiss, T. et al. Immunocytokines are a promising immunotherapeutic approach against glioblastoma. Sci. Transl. Med. 12, eabb2311 (2020).
Tzeng, A., Kwan, B. H., Opel, C. F., Navaratna, T. & Wittrup, K. D. Antigen specificity can be irrelevant to immunocytokine efficacy and biodistribution. Proc. Natl. Acad. Sci. USA 112, 3320–3325 (2015).
Pai, C. C. S. et al. Tumor-conditional anti-CTLA4 uncouples antitumor efficacy from immunotherapy-related toxicity. J. Clin. Invest. 129, 349–363 (2019).
Desnoyers, L. R. et al. Tumor-specific activation of an EGFR-targeting probody enhances therapeutic index. Sci. Transl. Med. 5, 207ra144 (2013).
Puskas, J. et al. Development of an attenuated interleukin-2 fusion protein that can be activated by tumour-expressed proteases. Immunology 133, 206–220 (2011).
Winkler, J., Abisoye-Ogunniyan, A., Metcalf, K. J. & Werb, Z. Concepts of extracellular matrix remodelling in tumour progression and metastasis. Nat. Commun. 11, 5120 (2020).
Jiang, W. et al. Expression of membrane type-1 matrix metalloproteinase, MT1-MMP in human breast cancer and its impact on invasiveness of breast cancer cells. Int. J. Mol. Med. 17, 583–590 (2006).
Wu, K.-P. et al. MT1-MMP is not a good prognosticator of cancer survival: evidence from 11 studies. Tumor Biol. 35, 12489–12495 (2014).
Isaacson, K. J., Jensen, M. M., Subrahmanyam, N. B. & Ghandehari, H. Matrix-metalloproteinases as targets for controlled delivery in cancer: an analysis of upregulation and expression. J. Control Release 259, 62–75 (2017).
Hashimoto, M. et al. CD8 T cell exhaustion in chronic infection and cancer: opportunities for interventions. Annu. Rev. Med. 69, 301–318 (2018).
Zou, W., Wolchok, J. D. & Chen, L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci. Transl. Med. 8, 328rv4 (2016).
Rovero, S. et al. DNA vaccination against rat Her-2/Neu p185 more effectively inhibits carcinogenesis than transplantable carcinomas in transgenic BALB/c mice. J. Immunol. 165, 5133–5142 (2000).
Acknowledgements
We thank Yang Wang for her technical assistance and providing reagents. We thank Benjamin Moon for the excellent editing. We thank Hui Su and Sai Yang for technical assistance in IBP. This work was partly supported by the funding from the National Science Foundation of China (No. 81803086) to Y. Liang.
Author information
Authors and Affiliations
Contributions
J.G., Y.L., H.P., and Y.-X.F. conceptualized the project and designed experiments. J.G. and Y.L. performed experiments. J.G. and Y.L. analyzed data. J.G., Y.L., H.P., and Y.-X.F. contributed to manuscript preparation. D.X., J.S., Y.C., and J.Z. provided technical or material supports. Y.L., H.P., and Y.-X.F. supervised the project.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Rights and permissions
About this article
Cite this article
Guo, J., Liang, Y., Xue, D. et al. Tumor-conditional IL-15 pro-cytokine reactivates anti-tumor immunity with limited toxicity. Cell Res 31, 1190–1198 (2021). https://doi.org/10.1038/s41422-021-00543-4
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s41422-021-00543-4
This article is cited by
-
The Evolving Applications of Bispecific Antibodies: Reaping the Harvest of Early Sowing and Planting New Seeds
BioDrugs (2025)
-
Targeting cytokine and chemokine signaling pathways for cancer therapy
Signal Transduction and Targeted Therapy (2024)
-
Thermal-responsive activation of engineered bacteria to trigger antitumor immunity post microwave ablation therapy
Nature Communications (2024)
-
Concurrent intratumoural Treg cell depletion and CD8+ T cell expansion via a cleavable anti-4-1BB–interleukin-15 fusion protein
Nature Biomedical Engineering (2024)
-
Interleukins in Epilepsy: Friend or Foe
Neuroscience Bulletin (2024)
