Treg Destabilization and Reprogramming: Implications for Cancer Immunotherapy

Abstract

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 proinflammatory signals such as IL6 and IFNγ. Under the right conditions, these signals can cause a rapid loss of suppressor activity and reprogramming of the Tregs into a proinflammatory 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. Cancer Res; 78(18); 5191-9. ©2018 AACR.

Figure 1.. Stabilizing and destabilizing signals for Tregs.

(A) Treg destabilizing signals. During immune-mediated inflammation, activated DCs secrete IL-6 and ligate the TCR on Tregs. In the same milieu, activated effector T cells produce IFNγ. Through various intermediate pathways, these upstream signals result in activation of PI3K; phosphorylation of Akt on the activating S473 and T308 sites; and activation of mTOR (mTORC1 and mTORC2 complexes). mTOR activation also feeds back to activate Akt, so the pathway functions as a loop. Activated Akt phosphorylates and inactivates the transcription factors FoxO3a and FoxO1, contributing to down-regulation of a suite of Treg-associated genes, and inhibition of the Treg suppressor phenotype. The IL-6-receptor, via induction of miR-17, also inhibits the transcription factor Eos, which is a binding partner for Foxp3, further destabilizing the suppressive phenotype. (B) Dominant stabilizing signals. In the tumor microenvironment, tolerogenic DCs and other APCs may express IDO (e.g., in response to local IFNγ, or induced by apoptotic cells). IDO degrades local tryptophan, activating the amino-acid sensitive kinase GCN2, which can inhibit mTOR. Low tryptophan and other metabolic deficiency states (e.g., low glucose) in the tumor microenvironment may also depress mTOR signaling. Surface receptors such as neuropilin-1 and PD-1 activate the PTEN phosphatase, which inhibits PI3K activity. In the absence of PI3K and mTORC2 activity, Akt is not phosphorylated and activated. Without Akt activity, FoxO1 and FoxO3a are allowed to remain active, and the Tregs are not destabilized. The FoxO1/FoxO3a axis also appears to feed back and up-regulate PD-1 and PTEN expression, thereby creating a self-reinforcing loop the stabilizes the suppressive Treg phenotype.