Tumor-Derived γδ Regulatory T Cells Suppress Innate and Adaptive Immunity through the Induction of Immunosenescence

Abstract

Fundamentally understanding the suppressive mechanisms utilized by different subsets of tumor-infiltrating regulatory T (Treg) cells is critical for the development of effective strategies for anti-tumor immunotherapy. γδ Treg cells have recently been identified in human diseases including cancer. However, the suppressive mechanisms and functional regulations of this new subset of unconventional Treg cells are largely unknown. In the current studies, we explored the suppressive mechanism(s) utilized by breast tumor-derived γδ Treg cells on innate and adaptive immunity. We found that γδ Treg cells induced immunosenescence in the targeted naïve and effector T cells, as well as dendritic cells (DCs). Furthermore, senescent T cells and DCs induced by γδ Treg cells had altered phenotypes, impaired functions and developed potent suppressive activities, further amplifying the immunosuppression mediated by γδ Treg cells. In addition, we demonstrated that manipulation of TLR8 signaling in γδ Treg cells can block γδ Treg-induced conversion of T cells and DCs into senescent cells in vitro and in vivo. Our studies identify the novel suppressive mechanism mediated by tumor-derived γδ Treg cells on innate and adaptive immunity, which should be critical for the development of strong and innovative approaches to reverse the tumor suppressive microenvironment and improve effects of immunotherapy.

Controlling T cell senescence in the tumor microenvironment for tumor immunotherapy

“…7 These studies clearly indicate that senescent tumor-infiltrating T cells are dysfunctional and could indirectly amplify and maintain the immunosuppressive effects mediated by tumor cells and Treg cells in the tumor microenvironment. [5][6][7] These results suggest a potential mechanism for the failures seen in multiple clinical trials of tumor vaccines and adoptive T cell therapies. In addition, the possibility of blocking the induction of T cell senescence and restoring the effector function of senescent T cells are critical goals for enhancing antitumor immunity.…”

“…5,6 In the current study, we further showed that multiple types of tumor cells, including breast cancer, melanoma, colon cancer, prostate cancer, ovarian cancer, and head and neck cancer, can also utilize the same mechanism as Treg cells and directly induce T cell senescence. 7 Senescent T cells develop significant phenotypic alterations, such as permanent loss of CD28 expression, cell cycle arrest, and secret proinflammatory and suppressive cytokines.…”

“…Identification of this novel suppressive mechanism utilized by tumor and Treg cells in our recent studies further suggests that blockage of senescence in tumor-specific T cells is also a critical checkpoint to control tumor suppression, which will provide a novel alternative target for cancer immunotherapy. [5][6][7] We have previously demonstrated that human Toll-like receptor 8 (TLR8) signaling completely reversed the suppressive functions of naturally occurring CD4 C CD25 C Treg and tumor-derived Treg cells. 10 In addition, our more recent studies have shown that TLR8 ligand treatment in Treg cells could prevent the senescence induction and reverse the suppressor function of senescent responder T cells.…”

“…7 Senescent T cells develop significant phenotypic alterations, such as permanent loss of CD28 expression, cell cycle arrest, and secret proinflammatory and suppressive cytokines. [4][5][6][7] More importantly, senescent T cells have exhibited functional changes, including defective killing abilities and the development of potent suppressive activity ( Fig. 1).…”

Empowering gamma delta T cells with antitumor immunity by dendritic cell-based immunotherapy

“…31,32 For example, tumor cells promote gd T cells to adopt a regulatory T cell (Treg) phenotype. Such gd Tregs damp antitumor immunity 33 and contribute to the immunosuppressive microenvironment that is characteristic of most tumor cells. 34 Deficient gd T cell functions have already been observed in various malignancies, including hematological, 20 liver, 35 breast 35 and gastric cancers.…”