Human γδ T lymphocytes induce robust NK cell–mediated antitumor cytotoxicity through CD137 engagement

Abstract

IntroductionNatural killer (NK) cells contribute to innate immune responses against virally infected and neoplastic cells. 1 NK cells usually recognize and attack tumor cells that lack major histocompatibility complex (MHC) class I. 2 Our previous studies in murine tumor models clearly demonstrated that gamma delta (␥␦) T lymphocytes play an important role in the regulation of antitumor NK-cell function. 3 Specifically, we have shown that ␥␦ T lymphocytes are required for the antitumor activity of NK cells in vivo. More recently, we have demonstrated that culturing human peripheral blood mononuclear cells (PBMCs) with agents that activate ␥␦ T lymphocytes induce NK cell-mediated cytotoxicity against tumors that normally resist NK killing. 4 These findings are concordant with other studies that show that ␥␦ T lymphocytes regulate the early phase of NK cell-mediated antibacterial responses in mice. 5 Taken in concert these data strongly suggest that ␥␦ T lymphocytes are important in the regulation of NK-cell functions.␥␦ T cells are characterized by the expression of a T-cell receptor (TCR) consisting of both gamma and delta chains, 6 and account for 1% to 10% of CD3 ϩ cells in the peripheral blood of healthy adults. 7 Approximately 70% of ␥␦ T lymphocytes express the V␥2V␦2 TCR and can be expanded and activated by phosphoantigens such as the cholesterol biosynthesis intermediate, isopentenylpyrophosphate (IPP), or synthetic bisphosphonates (eg, pamidronate disodium and zoledronic acid). [8][9][10] Upon stimulation, ␥␦ T lymphocytes acquire the capacity to destroy solid tumors of diverse origins such as squamous cell carcinoma of the head and neck (SCCHN), melanoma, colon cancer, and breast carcinoma, 4,[11][12][13] suggesting that ␥␦ T lymphocytes are important antitumor effector cells. The validity of this antitumor function is further supported by mouse models demonstrating that mice deficient in ␥␦ T cells have increased sensitivity to the development of methylcholanthrene (MCA)-induced tumors. 14 In addition, a recent pilot clinical study showed that ␥␦ T lymphocyte adoptive therapy for patients with advanced renal cell carcinoma was well tolerated and induced antitumor immune responses. 15 The antitumor effects of ␥␦ T lymphocytes are recognized to result from both direct killing of tumor targets and trans-activation of adaptive immune responses. For example, recent data demonstrate that activated ␥␦ T lymphocytes cause the maturation of dendritic cells that promote development of acquired immunity. 16 In addition, ␥␦ T cells are known to cross-present tumor antigens (Ags) to CD8 ϩ cytolytic T lymphocytes. 17,18 Despite their wellcharacterized role in mediating adaptive immune responses, the mechanisms by which ␥␦ T cells regulate cells of the innate immune system, such as NK cells, are unclear.In this report we demonstrate that ␥␦ T lymphocytes provide a costimulatory function for NK cells stimulated with suboptimal doses of immobilized human immuglobulin G1 (hIgG1). Costimulated NK cells display up-regulat...

Anti-γδ TCR antibody-expanded γδ T cells: a better choice for the adoptive immunotherapy of lymphoid malignancies

“…For example, recent data have demonstrated that cd T lymphocytes can induce robust natural killer cellmediated anti-tumour cytotoxicity. 22 Additionally, increasing evidence has demonstrated that cd T cells play an important role in the cross-talk between innate and adaptive immunity. cd T cells actively regulate the adaptive immune response through interactions with antigen presenting cells, such as dendritic cells.…”

Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status

“…Another mechanism might also enhance this phenomenon in vivo because CTX may exert its antitumor effects via pathways unrelated to EGFR‐targeting, such as through antibody‐dependent cell cytotoxicity (ADCC) 37. ZOL is also reported to increase the number of γδT cells, which are thought to activate ADCC 38. The evidence suggests that both reagents may synergistically enhance ADCC activity.…”

Functional expression of CD137 (4-1BB) on T helper follicular cells

“…It belongs to the tumor necrosis factor receptor (TNFR) family 1 and, upon crosslinking of the receptor by natural or artificial ligands, is endowed with co-stimulatory properties for T-cell activation. 2,3 Tissue distribution is broader than originally described, as CD137 has also been found to decorate activated natural killer (NK) cells, 4,5 B cells, 6 dendritic cells (DCs), 7 myeloid precursors, 8 mastocytes, 9 and tumor capillary endothelial cells. 10 There is only one described ligand, namely CD137L or 4-1BBL, 11 which acts as an agonistic moiety that crosslinks 4-1BB giving rise to activation signals.…”