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Building a better IL-10

The cytokine IL-10 suppresses inflammation and enhances the cytolytic activity of T cells. However, exogenously administered IL-10 has not been therapeutically successful, likely because of low bioavailability in the target tissue. IL-10 binds to a heterodimeric receptor composed of IL-10Rα subunits (to which it binds with high affinity) and IL-10Rβ subunits (to which it binds with lower affinity). Gorby et al. engineered an IL-10 variant with higher affinity for IL-10Rβ than that of wild-type IL-10. At low concentrations, this variant more potently triggered changes in gene expression in monocytes and CD8+ T cells that would be expected to suppress inflammation. CAR T cells cultured with this variant were more effective at killing acute myeloid leukemic cells. Thus, IL-10 therapy may become clinically feasible using variants with enhanced affinity for IL-10Rβ.

Abstract

Interleukin-10 (IL-10) is a dimeric cytokine with both immunosuppressive and immunostimulatory activities; however, IL-10–based therapies have shown only marginal clinical benefits. Here, we explored whether the stability of the IL-10 receptor complex contributes to the immunomodulatory potency of IL-10. We generated an IL-10 mutant with enhanced affinity for its IL-10Rβ receptor using yeast surface display. Compared to the wild-type cytokine, the affinity-enhanced IL-10 variants recruited IL-10Rβ more efficiently into active cell surface signaling complexes and triggered greater STAT1 and STAT3 activation in human monocytes and CD8+ T cells. These effects, in turn, led to more robust induction of IL-10–mediated gene expression programs at low ligand concentrations in both human cell subsets. IL-10–regulated genes are involved in monocyte energy homeostasis, migration, and trafficking and in CD8+ T cell exhaustion. At nonsaturating doses, IL-10 did not induce key components of its gene expression program, which may explain its lack of efficacy in clinical settings. Our engineered IL-10 variant showed a more robust bioactivity profile than that of wild-type IL-10 at low doses in monocytes and CD8+ T cells. Moreover, CAR-modified T cells expanded with the engineered IL-10 variant displayed superior cytolytic activity than those expanded with wild-type IL-10. Our study provides insights into how IL-10 receptor complex stability fine-tunes IL-10 biology and opens new opportunities to revitalize failed IL-10 therapies.

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Supplementary Material

Summary

Fig. S1. Yeast surface display selection for high-affinity monomeric IL-10 variants and recombinant expression of WT and high-affinity IL-10 monomeric and dimeric variants.
Fig. S2. Biophysical characterization of the high-affinity IL-10 variants.
Fig. S3. Single-molecule imaging of IL-10Rs by TIRF microscopy.
Fig. S4. Extended kinetics of IL-10 and variants in human monocytes.
Fig. S5. Analysis of gene expression profiles induced by WT IL-10 and high-affinity variants in human monocytes.
Fig. S6. Characterization of the IL-10–treated CD8+ T cell phenotype.
Fig. S7. Analysis of gene expression profiles induced by WT IL-10 and high-affinity variants in human CD8+ T cells.
Data file S1. RNA sequencing dataset for monocytes.
Data file S2. RNA sequencing dataset for CD8+ T cells.

Resources

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Science Signaling
Volume 13 | Issue 649
September 2020

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Received: 3 April 2020
Accepted: 20 August 2020

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Acknowledgments

We thank members of the Moraga, Mitra, Walter, Ferrand, and Piehler laboratories for helpful advice and discussion. We thank C. Taylor and C. Molina-Paris with help with statistical analyses Funding: This work was supported by the Wellcome Trust 203752/Z/16/Z (to C.G.), by the Wellcome-Trust-202323/Z/16/Z and ERC-206-STG grant (to I.M.), by EMBO (454-2017; to S.W.), by the Deutsche Forschungsgemeinschaft (SFB 944 and P8/Z to J.P.), and NIH (R01 AI143554 to M.R.W.). The Mitra laboratory is supported by the Projects Fondation ARC 2019 and La Ligue Contre le Cancer grants. Author contributions: C.G. and I.M. conceived the project. C.G., M.R.W., J.P., C.F., S.M., and I.M. wrote the manuscript. C.G. performed the engineering studies. C.G. and P.K.F. performed recombinant protein production and SPR binding measurements. C.G., S.W., and E.P. performed signaling and cellular experiments. S.W., J.S.B., and J.P. designed and performed single-particle microscopy experiments. C.G. designed, performed, and analyzed RNA sequencing studies. A.C., W.W., C.F., and S.M. designed, performed, and analyzed CAR T cell studies. Competing interests: C.G., S.M., and I.M. are inventors on patent application no. 2003428.6 submitted by the University of Dundee and Institut National de la Santé et de al Recherche Médicale that covers the IL-10 mutants. The other authors declare that they have no competing interests. Data materials and availability: The RNA sequencing data have been deposited in NCBI’s Gene Expression Omnibus with the accession number GSE146438, which includes all RAW and normalized files. All other data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials.

Authors

Affiliations

Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD15EH, UK.
Department of Biology and Center for Cellular Nanoanalytics (CellNanOs), University of Osnabrück, Barbarastraße 11, 49076 Osnabrück, Germany.
Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD15EH, UK.
Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France.
Elizabeth Pohler
Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD15EH, UK.
Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD15EH, UK.
Université de Lille, INSERM UMR1277 CNRS UMR9020–CANTHER and Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, France.
Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France.
Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35243, USA.
Suman Mitra
Université de Lille, INSERM UMR1277 CNRS UMR9020–CANTHER and Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, France.
Department of Biology and Center for Cellular Nanoanalytics (CellNanOs), University of Osnabrück, Barbarastraße 11, 49076 Osnabrück, Germany.
Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD15EH, UK.

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