Potential Use of γδ T Cell-Based Vaccines in Cancer Immunotherapy

Abstract

Immunotherapy is a fast advancing methodology involving one of two approaches: (1) compounds targeting immune checkpoints and (2) cellular immunomodulators. The latter approach is still largely experimental and features in vitro generated, live immune effector cells, or antigen-presenting cells. γδ T cells are known for their efficient in vitro tumor killing activities. Consequently, many laboratories worldwide are currently testing the tumor killing function of γδ T cells in clinical trials. Reported benefits are modest; however, these studies have demonstrated that large γδ T-cell infusions were well tolerated. Here, we discuss the potential of using human γδ T cells not as effector cells but as a novel cellular vaccine for treatment of cancer patients. Antigen-presenting γδ T cells do not require to home to tumor tissues but, instead, need to interact with endogenous, tumor-specific αβ T cells in secondary lymphoid tissues. Newly mobilized effector αβ T cells are then thought to overcome the immune blockade by creating proinflammatory conditions fit for effector T-cell homing to and killing of tumor cells. Immunotherapy may include tumor antigen-loaded γδ T cells alone or in combination with immune checkpoint inhibitors.

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

“…Activated Vc9/ Vd2 T cells turned out to be well equipped cross-presenting APCs capable of processing not only defined proteins but also complex material such as cell debris and whole bacteria, and shuttle endocytosed antigens into the cytosol for degradation by the proteasome [118][119][120]. As Vc9/Vd2 T cells retain their cytolytic potential when they acquire APC functions [127], this unique combination of direct target cytotoxicity and APC machinery allows for scenarios in which Vc9/Vd2 T cells would lyse transformed, stressed or infected cells, and take up and process released proteins for presentation to both CD4 + and CD8 + T cells, with enormous implications for novel immunotherapies and vaccines [128][129][130][131][132]. In this context, Himoudi et al [130] proposed a role for opsonizing antibodies in the efficient 'licensing' of Vc9/Vd2 T-APCs, by enhancing uptake of antibody-bound material via Fc receptors like CD16, which is expressed by Vc9/Vd2 T cells under certain stimulation conditions and on distinct subsets [133,134].…”

Editorial: “Recent advances in gamma/delta T cell biology: new ligands, new functions, and new translational perspectives”

“…Toward this end, the capacity of activated human γδ T cells to take up tumor-derived antigens and to present processed peptides to tumor antigen-specific CD8 + αβ T cells has been demonstrated ( 45 ). As discussed by Khan et al, the ease with which Vγ9Vδ2 T cells are expanded into large numbers in vitro offers an innovative strategy for the development of γδ T cell-based tumor vaccines ( 46 ).…”

The expanding family of noncanonical regulatory cell subsets

“…Ever since their discovery in 1986, γδ T cells have been neglected for a long time, partially because of technical and conceptual barriers. Since then γδ T cells have been shown to have diverse and potent physiological functions in various immune responses, including cytotoxicity, cytokine and chemokine production (i.e., IFN‐γ + γδ T cells and γδ T17 cells), B cell helper activity (by “Tfh‐likeVγ9Vδ2 T cells”), antigen‐presenting functions (by “γδ T‐APCs”), and regulatory activities (by “γδ‐Treg”) …”

“…Since then T cells have been shown to have diverse and potent physiological functions in various immune responses, including cytotoxicity, 87-89 cytokine and chemokine production (i.e., IFN-+ T cells and T17 cells), 90,91 B cell helper activity (by "Tfh-likeV 9V 2 T cells"), 92 antigenpresenting functions (by " T-APCs"), and regulatory activities (by " -Treg"). 93,94 A suppressor function for human T-cells was described as far back as 1989, 14 IL-17-producing T cells contribute to tumor progression by promoting angiogenesis and inducing the expansion of myeloid-derived suppressor cells (MDSCs). 107 T cells can also support G-CSF-dependent expansion of neutrophils, which inhibit CD8 cytotoxic T cells and thereby promote tumor cell metastases.…”