Oncogenic Transformation Can Orchestrate Immune Evasion and Inflammation in Human Mesenchymal Stem Cells Independently of Extrinsic Immune-Selective Pressure

Abstract

Immune escape is a hallmark of cancer, but whether it relies upon extrinsic immune-selective pressure or is inherently orchestrated by oncogenic pathways is unresolved. To address this question, we took advantage of an in vitro model of sequentially transformed human mesenchymal stem cells (hMSC). Neoplastic transformation in this model increased the natural immuneevasive properties of hMSC, both by reducing their immunogenicity and by increasing their capacity to inhibit mitogen-driven T-cell proliferation. We also found that IFNg signaling was globally affected in transformed hMSC. As a consequence, the natural inhibitory effect of hMSC on T-cell proliferation switched from an inducible mechanism depending on IFNg signaling and mediated by indoleamine 2,3-dioxygenase to a constitutive mechanism that relied upon IL1b involving both secreted and membraneexpressed molecules. After transformation, increased IL1b expression both sustained the immunosuppressive properties of hMSC and increased their tumorigenicity. Thus, in this model system, IL1b acted as intrinsic inflammatory mediator that exerted an autocrine influence on tumor growth by coordinately linking immune escape and tumorigenicity. Collectively, our findings show how oncogenes directly orchestrate inflammation and immune escape to drive the multistep process of cancer progression, independently of any need for immunoediting in the tumor microenvironment. Cancer Res; 75(15); 3032-42. Ó2015 AACR.

The Roles of Mesenchymal Stromal/Stem Cells in Tumor Microenvironment Associated with Inflammation

“…Despite disrupted IFN- γ signalization, activity of IL-1 β sustains immunosuppressive potential of transformed MSCs. Namely, in vitro transformed MSCs possess higher expression of IL-1 β , which acts as intrinsic mediator of inflammation and masters relation of tumorigenicity and immune surveillance escape in an autocrine manner [105]. Additionally, increment of IL-1 β in TME can lead to stabilization of HIF-1 in tumor cells and contribute to tumorigenesis through activation of genes implicated in metabolism, angiogenesis, and migration [98].…”

Effects of microenvironment and biological behavior on the paracrine function of stem cells

“… 34 Hypoxia can increase the secretion of IL-1β by hMSCs in the TME, which inhibits T cell proliferation to induce inflammation and immune escape. 35 …”