Treg Destabilization and reprogramming: Implications for cancer immunotherapy

Regulatory T cells (Tregs) are an important contributor to the immunosuppressive tumor microenvironment. To date, however, they have been difficult to target for therapy. One emerging new aspect of Treg biology is their apparent functional instability in the face of certain acute proin-flammatory signals such as IL6 and IFNg. Under the right conditions, these signals can cause a rapid loss of suppressor activity and reprogramming of the Tregs into a proin-flammatory phenotype. In this review, we propose the hypothesis that this phenotypic modulation does not reflect infidelity to the Treg lineage, but rather represents a natural, physiologic response of Tregs during beneficial inflammation. In tumors, however, this inflammation-induced Treg destabilization is actively opposed by dominant stabilizing factors such as indoleamine 2,3-dioxygenase and the PTEN phosphatase pathway in Tregs. Under such conditions, tumor-associated Tregs remain highly suppressive and inhibit cross-presentation of tumor antigens released by dying tumor cells. Interrupting these Treg stabilizing pathways can render tumor-associated Tregs sensitive to rapid destabilization during immunotherapy, or during the wave of cell death following chemotherapy or radiation, thus enhancing antitumor immune responses. Understanding the emerging pathways of Treg stabilization and destabilization may reveal new molecular targets for therapy.