Pulling the Trigger on the Tumor‘s Bodyguards: What Puts Tregs Out of Action?

Abstract

Tumor escape is still a major opponent to the success of many immune interventions in cancer, and a full body of studies has revealed Foxp3 Treg cells to act as bodyguards in the tumor microenvironment, highlighting their critical role in the failure of cancer immunotherapy. As the Treg field becomes more advanced, particularly with regard to the essential function of Treg cells in the maintenance of immunological self-tolerance and autoimmunity [1], recent studies showed compelling evidence conferring a critical role to Treg cells in the tumor’s defense against the efforts for an effective cancer immuno therapy [2,3]. However, in order to pull the trigger on the tumor’s bodyguards, one needs molecular markers for specific Treg cell targeting and for prevention of collateral damage. Therefore, the search is still under way to find a highly specific cell surface marker, paving the way for Treg cell depletion and attenuation of Treg cell suppressive function. In addition, one would like to render effector T cells refractory to Treg cell-mediated suppression. The common goal of all strategies is the attempt to tip the balance towards an effective and specific cancer immunotherapy without inducing unwanted side effects. High frequencies of Treg cells within the tumor microenvironment have been described in several types of tumors, and have been associated with poor prognosis and reduced survival [2,3], raising the question of whether the tumors recruit Treg cells or generate them from precursors within the tumor microenvironment. Both scenarios seem to be the cause. On the one hand, tumors may induce protection by generating Treg cells from naive T cells via production of TGF-b [3–5], which has been shown to induce the differentiation of naive T cells into Treg cells [6]. Hence, an attack at TGF-b may enhance antitumor immunity. On