γδ T Cells in the Tumor Microenvironment—Interactions With Other Immune Cells

Abstract

A growing number of studies have shown that γδ T cells play a pivotal role in mediating the clearance of tumors and pathogen-infected cells with their potent cytotoxic, cytolytic, and unique immune-modulating functions. Unlike the more abundant αβ T cells, γδ T cells can recognize a broad range of tumors and infected cells without the requirement of antigen presentation via major histocompatibility complex (MHC) molecules. Our group has recently demonstrated parts of the mechanisms of T-cell receptor (TCR)-dependent activation of Vγ9Vδ2+ T cells by tumors following the presentation of phosphoantigens, intermediates of the mevalonate pathway. This process is mediated through the B7 immunoglobulin family-like butyrophilin 2A1 (BTN2A1) and BTN3A1 complexes. Such recognition results in activation, a robust immunosurveillance process, and elicits rapid γδ T-cell immune responses. These include targeted cell killing, and the ability to produce copious quantities of cytokines and chemokines to exert immune-modulating properties and to interact with other immune cells. This immune cell network includes αβ T cells, B cells, dendritic cells, macrophages, monocytes, natural killer cells, and neutrophils, hence heavily influencing the outcome of immune responses. This key role in orchestrating immune cells and their natural tropism for tumor microenvironment makes γδ T cells an attractive target for cancer immunotherapy. Here, we review the current understanding of these important interactions and highlight the implications of the crosstalk between γδ T cells and other immune cells in the context of anti-tumor immunity.

γδ T Lymphocytes as a Double-Edged Sword—State of the Art in Gynecological Diseases

“…Which one of the two possibilities takes place depends on the tumor microenvironment (TME) and the subpopulation of γδ T lymphocytes ( Figure 1 .). Interestingly, γδ T lymphocytes can switch phenotypes in response to TME signals [ 10 , 11 ]. Immune system cells are exposed in the TME to many signals that determine their immunophenotype and can modulate their functions [ 12 ].…”

“…The subsets of Vγ9Vδ2 T cells have strong antitumor activity, explaining their wide usage in clinical settings. Numerous clinical studies have used aminobisphosphonates (e.g., zoledronate and pamidronate) to inhibit farnesyl pyrophosphate synthase in the mevalonate pathway to promote the accumulation of isopentenyl pyrophosphate (IPP) in cells, or synthetic phosphoantigen analogues, such as bromohydrin pyrophosphate (BrHPP) and 2-methyl-3-butenyl-1-pyrophosphate (2M3B1PP), to activate Vγ9Vδ2 + T cells in patients with malignant tumors [ 10 ].…”

Cationic Polyethyleneimine (PEI)–Gold Nanocomposites Modulate Macrophage Activation and Reprogram Mouse Breast Triple-Negative MET-1 Tumor Immunological Microenvironment

“…Tumors exhibit a complex stroma where several cellular and matrix components play an important role in sustaining tumor cell growth and survival. Immune cells such as T, B, macrophages, and dendritic cells interact with each other and with tumor cells in a paracrine manner through soluble factors such as cytokines and chemokines [ 1 ], by communicating through extracellular vesicles [ 2 ], or by direct contact cell-to-cell through receptor–ligand cognates [ 3 ]. Other cells such as fibroblasts contribute to the intricate tumor microenvironment (TME) by supporting not only tumor cell growth and immune response suppression through different soluble factors [ 4 , 5 , 6 ] but also by secreting extracellular matrix components, e.g., collagens and mucin, that affect tumor stiffness and interstitial pressure, a documented characteristic of desmoplastic tumors [ 4 , 7 ].…”

192 Characterization of antibodies against BTN2A1 for Vδ2+γδ T cell-based tumor immunotherapy

“…Background Human gd T cells are ideal candidates for tumor immunotherapy because of their natural tropism for tumor microenvironment, elicit rapid innate-like immune responses upon tumor recognition and the ability to orchestrate other tumor-infiltrating immune cells for tumor cell killing. 1 Our group has recently defined aspects of the mechanism of T-cell receptor (TCR) dependent activation of Vg9Vd2 + T cells by tumors following the presentation of phosphoantigens via the B7 immunoglobulin family-like butyrophilin 2A1 (BTN2A1) and BTN3A1. 2 Dysregulation of the mevalonate pathway in tumors can cause activation of Vg9Vd2 + T cells via phosphoantigen accumulation and induces gd T cell chemotaxis toward tumor cells.…”

“…[5][6][7][8] More recently, agonist antibodies against BTN3A (e.g., clone 20.1, ICT-01 and CTX-2026) have been identified and used as a phosphoantigen-independent approach to activate Vg9Vd2 + T cells for targeted cell killing. 1 Methods We are currently characterizing a number of anti-BTN2A1 antibodies that can potentially be used to modulate the activity of Vg9Vd2 + T cells in in vitro assays.…”