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 immune evasive properties of hMSC, both by reducing their immunogenicity and by increasing their capacity to inhibit mitogen driven T-cell proliferation. We also found that IFN-γ 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 IFN-γ signaling and mediated by indoleamine 2,3-dioxygenase (IDO) to a constitutive mechanism that relied upon IL-1β involving both secreted and membrane-expressed molecules. After transformation, increased IL-1β expression both sustained the immunosuppressive properties of hMSC as well as increased their tumorigenicity. Thus, in this model system IL-1β 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.
