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

Abstract

These authors equally contributed to the work.Keywords: gd T cell, cancer, DC-mediated gd T cell activation, dendritic cell, immunotherapy Abbreviations: gd, gamma delta; BCG, Bacillus Calmette-Guerin; BrHPP, bromohydrin pyrophosphate; CTL, cytotoxic T lymphocyte; DC, dendritic cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; HIV, human immunodeficiency virus; HMBPP, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate; iDC, immature DC; IFN, interferon; IL, interleukin; IPP, isopentyl pyrophosphate; mDC, myeloid dendritic cell; MHC, major histocompatibility complex; mo-DC, monocyte-derived dendritic cell; pDC, plasmacytoid dendritic cell; PD, programmed cell death protein; TCR, T-cell receptor; Th, T-helper cell; TLR, toll-like receptor; TNF, tumor necrosis factor; Treg, regulatory T cellGamma delta (gd) T cells are the all-rounders of our immune-system with their major histocompatibility complexunrestricted cytotoxicity, capacity to secrete immunostimulatory cytokines and ability to promote the generation of tumor antigen-specific CD8 C and CD4 C T cell responses. Dendritic cell (DC)-based vaccine therapy has the prospective to harness these unique features of the gd T cells in the fight against cancer. In this review, we will discuss our current knowledge on DC-mediated gd T cell activation and related opportunities for tumor immunologists.

In the Absence of a TCR Signal IL-2/IL-12/18-Stimulated γδ T Cells Demonstrate Potent Anti-Tumoral Function Through Direct Killing and Senescence Induction in Cancer Cells

“…γδ T cells infiltrate a variety of cancers and modulate anti-tumor immunity [41][42][43][44], and a recent extensive gene expression study identified tumor-infiltrating γδ T cells as the most favorable prognostic marker in many types of cancer [45]. Along with their unique beneficial features such as the production of abundant pro-inflammatory cytokines, including IFN-γ and TNF-α, MHC-independent recognition of antigens, direct lysis of tumor cells, antibody-dependent cellular cytotoxicity (ADCC), and antigen presentation capacity [46], γδ T cells are proposed to constitute a promising target in cancer immunotherapy. However, adoptive transfer of pharmacologically manipulated γδ T cells did not hold promise.…”

Regulatory and effector functions of gamma–delta (γδ) T cells and their therapeutic potential in adoptive cellular therapy for cancer

“…The effector function of γδ T cells in the tumor microenvironment is induced by the interaction of γδ TCR with the stress‐induced molecules expressed on tumor cells . Tumor cells have an active mevalonate pathway and produce isoprenoids such as IPP, which help in cell growth and survival .…”

“…50,51 The effector function of gd T cells in the tumor microenvironment is induced by the interaction of gd TCR with the stress-induced molecules expressed on tumor cells. 25,26,52 Tumor cells have an active mevalonate pathway 53 and produce isoprenoids such as IPP, which help in cell growth and survival. 54 Many of the mevalonate pathway intermediates, including IPP, were shown to activate human Vg9Vd2 T cells and promote anti-tumor response.…”

Necroptosis of Dendritic Cells Promotes Activation of γδ T Cells

“…Furthermore, growing evidence suggests that many of these self-ligands may be induced under conditions of stress in a variety of cell types [1]. As such γδ T cells may have evolved to respond to certain host-derived molecules that are exposed and/or upregulated during the early phases of infection, sterile inflammation, tumor development, or even cell death [5]. …”