Oncotarget

Research Papers: Immunology:

Activated T cells sustain myeloid-derived suppressor cell-mediated immune suppression

Laura Pinton, Samantha Solito, Vera Damuzzo, Samuela Francescato, Assunta Pozzuoli, Antonio Berizzi, Simone Mocellin, Carlo Riccardo Rossi, Vincenzo Bronte and Susanna Mandruzzato _

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Oncotarget. 2016; 7:1168-1184. https://doi.org/10.18632/oncotarget.6662

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Abstract

Laura Pinton1,*, Samantha Solito1,*, Vera Damuzzo1, Samuela Francescato2, Assunta Pozzuoli3, Antonio Berizzi3, Simone Mocellin3,4, Carlo Riccardo Rossi3,4, Vincenzo Bronte5 and Susanna Mandruzzato1,6

1 Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy

2 Clinic of Pediatric Hemato-Oncology, Department of Women’s and Children’s Health, University of Padova, Padova, Italy

3 Surgery Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy

4 Surgical Oncology Unit, Veneto Institute of Oncology - IOV-IRCSS, Padua, Italy

5 University of Verona, Department of Pathology and Diagnostic, Section of Immunology, Verona, Italy

6 Veneto Institute of Oncology - IOV-IRCSS, Padua, Italy

* These authors have contributed equally to this work

Correspondence to:

Susanna Mandruzzato, email:

Keywords: MDSC, immune suppression, tolerance, immune regulatory pathways, tumor microenvironment, Immunology and Microbiology Section, Immune response, Immunity

Received: August 28, 2015 Accepted: November 22, 2015 Published: December 18, 2015

Abstract

The expansion of myeloid derived suppressor cells (MDSCs), a suppressive population able to hamper the immune response against cancer, correlates with tumor progression and overall survival in several cancer types. We have previously shown that MDSCs can be induced in vitro from precursors present in the bone marrow and observed that these cells are able to actively proliferate in the presence of activated T cells, whose activation level is critical to drive the suppressive activity of MDSCs. Here we investigated at molecular level the mechanisms involved in the interplay between MDSCs and activated T cells. We found that activated T cells secrete IL-10 following interaction with MDSCs which, in turn, activates STAT3 phosphorylation on MDSCs then leading to B7-H1 expression. We also demonstrated that B7-H1+ MDSCs are responsible for immune suppression through a mechanism involving ARG-1 and IDO expression. Finally, we show that the expression of ligands B7-H1 and MHC class II both on in vitro-induced MDSCs and on MDSCs in the tumor microenvironment of cancer patients is paralleled by an increased expression of their respective receptors PD-1 and LAG-3 on T cells, two inhibitory molecules associated with T cell dysfunction. These findings highlight key molecules and interactions responsible for the extensive cross-talk between MDSCs and activated T cells that are at the basis of immune suppression.


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