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Nat Immunol. 2019 Apr 1. doi: 10.1038/s41590-019-0346-9. [Epub ahead of print]

Adaptive plasticity of IL-10+ and IL-35+ Treg cells cooperatively promotes tumor T cell exhaustion.

Author information

1
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
2
Department of Inflammation and Oncology, Discovery Research, Amgen, South San Francisco, CA, USA.
3
Program in Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
4
Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
5
Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.
6
The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
7
Department of Biostatistics, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA.
8
Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
9
Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
10
Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
11
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
12
Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
13
Cancer Immunology & Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
14
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. dvignali@pitt.edu.
15
Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. dvignali@pitt.edu.
16
Cancer Immunology & Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. dvignali@pitt.edu.

Abstract

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.

PMID:
30936494
DOI:
10.1038/s41590-019-0346-9

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