T2 ribonuclease-mediated tumor suppression: an evolutionary conserved process involving a cross-talk between cancer cells and the immune system

The link between cancer development and immune system dysregulation has long been established, and both the innate and adaptive immune systems are widely acknowledged to establish a complex crosstalk in vivo with cancer cells, which might culminate into a pro- or anti-tumorigenic response. In this context, cells belonging to the monocyte/macrophage lineage represent a key cellular component of the innate immune system involved in the control of the tumorigenic process, since advanced human tumors are frequently infiltrated with Tumor-Associated Macrophages (TAMs) which actively contribute to tumor growth and dissemination. However, the long established functional plasticity displayed by macrophages can provide these cells with a marked anti-tumor properties as well. Thus, experimental approaches aimed at promoting a macrophage shift in vivo from pro-tumor to anti-tumor phenotype represent a deeply investigated research field to develop immune system-mediated oncosuppresive therapies. The human RNASET2 oncosuppressor gene has recently emerged as a potential tool for macrophage-mediated tumor suppression. T2 Rnases represent very ancient, pleiotropic and evolutionary conserved enzymes involved in a wide range of biological processes, among which host defense is frequently observed. A key role for human RNASET2 in the regulation of macrophage activity in both in vitro and in vivo experimental models has been recently reported. Of note, the ability of RNASET2 to tune the macrophage phenotype has been recently observed in both vertebrate and invertebrate experimental model, thus pointing at a very ancent role for T2 Rnases in the modulation of the innate immune system. Moreover, recent reports suggest a functional role for RNASET2 in a broader range of immune cell types, pointing at T2 Rnases as a putative regulators of several functional features within the immune system.