Lineage Reprogramming of Effector Regulatory T Cells in Cancer

Abstract

Regulatory T-cells (Tregs) are important for maintaining self-tolerance and tissue homeostasis. The functional plasticity of Tregs is a key feature of this lineage, as it allows them to adapt to different microenvironments, adopt transcriptional programs reflective of their environments and tailor their suppressive capacity in a context-dependent fashion. Tregs, particularly effector Tregs (eTregs), are abundant in many types of tumors. However, the functional and transcriptional plasticity of eTregs in tumors remain largely to be explored. Although depletion or inhibition of systemic Tregs can enhance anti-tumor responses, autoimmune sequelae have diminished the enthusiasm for such approaches. A more effective approach should specifically target intratumoral Tregs or subvert local Treg-mediated suppression. This mini-review will discuss the reported mechanisms by which the stability and suppressive function of tumoral Tregs are modulated, with the focus on eTregs and a subset of eTregs, follicular regulatory T (TFR) cells, and how to harness this knowledge for the future development of new effective cancer immunotherapies that selectively target the tumor local response while sparing the systemic side effects.

Contribution of Dysregulated B-Cells and IgE Antibody Responses to Multiple Sclerosis

“…T FH cells have been shown to undergo progressive maturation after entering the GC to regulate GC B-cell differentiation, starting with an IL-21 + T FH cells that enable the selection of high-affinity antibodies to become IL-4 + T FH cells that promote the differentiation of ASCs, including IgE-producing cells ( 88 ). Although T FR cells can positively induce IgE under certain settings ( 89 , 90 ), we and others have reported that T FR cells, particularly Blimp1 + T FR cells, are key suppressors of IgE production ( 42 , 63 , 91 – 95 ). Using a unique T FR cell-deleter mouse strain, T FR cells have been demonstrated to control IgG and IgE responses and regulate IL-13-producing T FH cell-induced IgE specifically in house dust mite models ( 94 ).…”

Reprogramming the tumor microenvironment with biotechnology

“…PD-1 and CTLA-4 are the most representative immune checkpoints [ 59 ]. High PD-1 expression can be unfavorable in suppressing Tregs activity [ 65 ]. Moreover, anti-PD-1 and anti-PD-L1 can promote the anti-tumor activity of CD8 + T cells by suppressing Tregs activity.…”

“…Thus, controlling PD-1 expression is a potential clinical strategy. CTLA-4 functions as an immune checkpoint and interrupts immune responses and APCs [ 65 , 67 ]. CTLA-4 also represses the immune responses and promotes the survival of tumor cells [ 59 ].…”

Drug Resistance in Cancers: A Free Pass for Bullying

“…CD4 + CD25 + Foxp3 + represents a classical combined marker of Tregs [ 19 ]. CD4 + CD25 + Foxp3 + Tregs are the preponderating T cells that respond to cancers, outpacing CD8 + cytotoxic T lymphocytes (CTLs) during drug resistance development [ 20 ]. In particular, Tregs dampened CTL translocation to the tumor cells through collaborations with M2 macrophages and CAFs [ 21 ].…”