Regulatory T cells (Treg cells) maintain host self-tolerance but are a major barrier to effective cancer immunotherapy. Treg cells subvert beneficial anti-tumor immunity by modulating inhibitory receptor expression on tumor-infiltrating lymphocytes (TILs); however, the underlying mediators and mechanisms have remained elusive. Here, we found that the cytokines IL-10 and IL-35 (Ebi3–IL-12α heterodimer) were divergently expressed by Treg cell subpopulations in the tumor microenvironment (TME) and cooperatively promoted intratumoral T cell exhaustion by modulating several inhibitory receptor expression and exhaustion-associated transcriptomic signature of CD8+ TILs. While expression of BLIMP1 (encoded by Prdm1) was a common target, IL-10 and IL-35 differentially affected effector T cell versus memory T cell fates, respectively, highlighting their differential, partially overlapping but non-redundant regulation of anti-tumor immunity. Our results reveal previously unappreciated cooperative roles for Treg cell-derived IL-10 and IL-35 in promoting BLIMP1-dependent exhaustion of CD8+ TILs that limits effective anti-tumor immunity.
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Bulk RNAseq datasets of CD8+ T cells and Treg cell subpopulations have been deposited in the GEO with the accession code GSE127735. Single-cell RNAseq dataset has been deposited in the GEO with the accession code GSE126184. The RNAseq data sets reported by other studies used to cross-examine with our sequencing data in this study were obtained from GSE9650 and GSE84105. The main data supporting the findings of this study are available in the article and its Supplementary Figures. Data are available from the corresponding authors upon appropriate and reasonable request.
Computational and mathematical codes used in the RNAseq analyses supporting the findings of this study are available in the article. Additional information is available from corresponding author on reasonable and appropriate request.
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The authors wish to thank H. Shen, D. Falkner and A. Yates from the Immunology Flow Core for cell sorting; E. Brunazzi and the staff of the Division of Laboratory Animals for animal husbandry; A. Cillo for helpful suggestions regarding scRNAseq analysis; W. Horne, J. Kolls and the University of Pittsburgh HSCRF Genomics Research Core for assistance with sequencing and A. Menk and G. Delgoffe at the Universtiy of Pittsburgh for generation and provision of the BrafPten (clone 24) cell line for tumor growth experiments. The authors also wish to thank the Department of Cardiothoracic Surgery at the University of Pittsburgh, in particular, J. Ward for her help in coordination and gathering patient consents, as well as the Department of Cardiothoracic Surgery at the University of Colorado and the University of Colorado SPORE for providing some samples. This work was supported by the National Institutes of Health (grant nos. R01 CA203689 and P01 AI108545 to D.A.A.V.), NCI Comprehensive Cancer Center Support CORE grant (no. CA047904 to D.A.A.V.) and an SRA from Tizona Therapeutics. This work also benefitted from the Immunology Department Flow Cytometry Core SPECIAL BD LSR FORTESSA funded by NIH grant no. 1S10OD011925-01 (L. Borghesi, Department of Immunology). This project also used the Hillman Cancer Center Immunologic Monitoring and Cellular Products Laboratory that is supported in part by award no. P30 CA047904.
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Nature Immunology (2019)