Pinton Laura, Solito Samantha, Damuzzo Vera, Francescato Samuela, Pozzuoli Assunta, Berizzi Antonio, Mocellin Simone, Rossi Carlo Riccardo, Bronte Vincenzo, Mandruzzato Susanna
Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
Clinic of Pediatric Hemato-Oncology, Department of Women's and Children's Health, University of Padova, Padova, Italy.
Oncotarget. 2016 Jan 12;7(2):1168-84. doi: 10.18632/oncotarget.6662.
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.
髓源性抑制细胞（MDSCs）是一类能够抑制针对癌症的免疫反应的细胞群体，其扩增与多种癌症类型的肿瘤进展和总生存期相关。我们之前已经表明，MDSCs可在体外由骨髓中的前体细胞诱导产生，并且观察到这些细胞在活化T细胞存在的情况下能够积极增殖，而活化T细胞的活化水平对于驱动MDSCs的抑制活性至关重要。在此，我们在分子水平上研究了MDSCs与活化T细胞之间相互作用所涉及的机制。我们发现，活化T细胞在与MDSCs相互作用后分泌IL-10，这反过来又激活了MDSCs上的STAT3磷酸化，进而导致B7-H1表达。我们还证明，B7-H1+ MDSCs通过涉及ARG-1和IDO表达的机制负责免疫抑制。最后，我们表明，在体外诱导的MDSCs以及癌症患者肿瘤微环境中的MDSCs上，配体B7-H1和MHC II类分子的表达与T细胞上各自受体PD-1和LAG-3的表达增加同时出现，这两种抑制性分子与T细胞功能障碍相关。这些发现突出了负责MDSCs与活化T细胞之间广泛相互作用的关键分子和相互作用，而这些相互作用是免疫抑制的基础。
