Tregs in Tumor Escape Checkpoints

Specific T cell populations have suppressive/regulatory cells known as Regulatory T-cell or Tregs (Previously known as suppressor T-cell). Among them CD4+ regulatory T cells (Tregs) basically has two different subsets Tr1 and Th3 cells which are differentiated by their distinct suppressive mechanisms. The thymus-derived Tregs or natural Tregs (nTregs) express CD4 and high CD25 with FOXP3 (Forkhead Box-P3) to be a key regulatory gene (Ref.1). Apart from these, other markers of Treg include CTLA4 (Cytotoxic T-Lymphocyte-Associated protein-4), GITR (Glucocorticoid-Induced TNFR-Related protein) and LAG-3 (Lymphocyte Activation Gene-3). Treg cells are implicated in the development of autoimmunity, allergy and rejection of organ transplants, as well as the suppression of immune responses to cancer. Down regulation of the antigen presentation machinery has been considered as the most common strategy exploited by tumors cells to escape T cell control.

The key elements engaged in tumor escape include Treg cells, DCs (Dendritic cells) and NKT (Natural Killer Cells). CD4+ NKT cells suppress CTL (Cytotoxic T Lymphocytes)-effector functions by the secretion of IL-13 (Interleukin-13) and TGF-Beta (Transforming Growth Factor-Beta) which later activates IL-4R -STAT6 (Signal Transducer and Activator of Transcription-6) pathway (Ref.2&3). Tumor environmental factors, such as VEGF (Vascular Endothelial Growth Factor), IL-10 (Interleukin-10) and TGF-Beta suppress DCs differentiation and function, resulting in immature and/or partially differentiated DCs (Ref.4). These factors also induce STAT3 (Signal Transducer and Activator of Transcription-3) activation in DCs which in turn leads to impaired antigen-specific T cell levels of responses. These immature DCs dampens pre-existing antigen-specific effector T cell function in the presence of SOCS1 (Suppressors of cytokine signaling 1), Arginase and IDO (Indoleamine 2, 3-dioxygenase) (Ref.4, 5, 6&3). Again, pDCs (Plasmacytoid DCs) expresses the enzyme IDO that prevent the clonal expansion of T cells and promote T cell death. Tumor micro environmental CCL22 (Chemokine (C-C motif) Ligand-22) mediates trafficking of Treg cells into the tumor. In this process Treg cells express functional CCR4 (Chemokine (C-C motif) Receptor-4), the receptor for CCL22 , and migrate towards it in response to CCL22 in the tumor microenvironment, which is produced by tumor cells, in the presence of IDO and TGF-Beta . On activation, Treg cells proliferate and gain suppressive activity. Treg cells suppress both the innate and the adaptive immune response, including the priming and effector phase of both CD4 and CD8 T cells. Tumor-associated Macrophages and Dendritic cells also play a role in the expansion of Treg cells. Such expansion occurs through the proliferation of pre-existing Treg cells and the conversion of naive precursors into induced Treg cells in the presence of TGF-Beta and IDO (Ref.4, 5&7). Galectin-1 and Gangliosides along with TGF-Beta , PGE2 (Prostaglandin-E2) and IL-10 inhibits T cell effector functions by inducing T cell apoptosis (Ref.3). The suppressive molecules including VEGF, IL-10 , TGF-Beta , Arginase, IDO , PGE2, COX2 IL-12 and co signaling molecules such as CD80 or CD86 . These CTLs, when in sufficient abundance and directed against the appropriate tumor antigens, eradicate the tumor. Although the induced CTLs initially combat the tumor, they then fail as dysfunctional DC-induced Tregs ultimately inhibiting antitumor CTLs promoting tumor escape (Ref.8).

Treg cells within the tumor microenvironment are a crucial component of the tumor immunosuppressive network, the clinical depletion of Treg cells in patients with tumors can become a promising strategy for boosting TAA (Tumor-Associated Antigen)-specific immunity. Depletion of CD25+ cells using an antibody against CD25 results in improved tumor rejection. CTLA4 attenuates the potency of TAA-specific T-cell immunity. Administration of an antibody that blocks CTLA4 function inhibits the growth of moderately immunogenic tumors. Denileukin diftitox (Ontak) is a ligand toxin fusion, which depletes CD4+CD25+ TReg cells. Denileukin diftitox represents the first agent that is potentially useful for humans as blockade of Treg-cell-specific transport represents a novel means to augment tumor immunity (Ref.5).