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Lactate modulates CD4+ T-cell polarization and induces an immunosuppressive environment, which sustains prostate carcinoma progression via TLR8/miR21 axis

Oncogene volume 38, pages 3681–3695 (2019)Cite this article

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Abstract

Leukocyte infiltration plays an active role in controlling tumor development. In the early stages of carcinogenesis, T cells counteract tumor growth. However, in advanced stages, cancer cells and infiltrating stromal components interfere with the immune control and instruct immune cells to support, rather than counteract, tumor malignancy, via cell–cell contact or soluble mediators. In particular, metabolites are emerging as active players in driving immunosuppression. Here we demonstrate that in a prostate cancer model lactate released by glycolytic cancer-associated fibroblasts (CAFs) acts on CD4+ T cells, shaping T-cell polarization. In particular, CAFs exposure (i) reduces the percentage of the antitumoral Th1 subset, inducing a lactate-dependent, SIRT1-mediated deacetylation/degradation of T-bet transcription factor; (ii) increases Treg cells, driving naive T cells polarization, through a lactate-based NF-kB activation and FoxP3 expression. In turn, this metabolic-based CAF-immunomodulated environment exerts a pro-invasive effect on prostate cancer cells, by activating a previously unexplored miR21/TLR8 axis that sustains cancer malignancy.

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Acknowledgements

The work was supported by Fondazione Umberto Veronesi to GC and AM, Associazione Italiana Ricerca sul Cancro (AIRC) (grant 8797 to PC), AIRC and Fondazione Cassa di Risparmio di Firenze (grant 19515 to PC and AM), Istituto Toscano Tumori (grant 0203607 to PC), Programma operativo regionale Obiettivo “Competitività regionale e occupazione” della Regione Toscana cofinanziato dal Fondo europeo di sviluppo regionale 2007-2013 (POR CReO FESR 2007-2013, grant to PC). The authors thank Dr. Lavinia Ferrone for technical support.

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  1. These authors contributed equally: G Comito, A Iscaro, E Giannoni, P Chiarugi

Authors and Affiliations

  1. Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134, Florence, Italy

    G. Comito, M. Bacci, A. Morandi, L. Ippolito, M. Parri, E. Giannoni & P. Chiarugi

  2. Department of Oncology and Metabolism, University of Sheffield, Medical School, Beech Hill Road, Sheffield, UK

    A. Iscaro

  3. Histopathology and Molecular Diagnostics, University Hospital Careggi, Largo Brambilla, 3, 50134, Florence, Italy

    I. Montagnani & M. R. Raspollini

  4. Department of Urological Robotic Surgery and Renal Transplantation, University of Florence, Careggi Hospital, Florence, 50134, Italy

    S. Serni

  5. Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Leipziger Str. 44, D-39120, Magdeburg, Germany

    L. Simeoni

  6. Tuscany Tumor Institute (ITT) and Excellence Centre for Research, Transfer and High Education DenoTHE, Florence, 50134, Italy

    P. Chiarugi

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Comito, G., Iscaro, A., Bacci, M. et al. Lactate modulates CD4+ T-cell polarization and induces an immunosuppressive environment, which sustains prostate carcinoma progression via TLR8/miR21 axis. Oncogene 38, 3681–3695 (2019). https://doi.org/10.1038/s41388-019-0688-7

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