Glioblastoma cells potentiate the induction of the Th1-like profile in phosphoantigen-stimulated γδ T lymphocytes

Rosso, David Antonio; Rosato, Micaela; Iturrizaga, Juan; González, Nazareno; Shiromizu, Carolina Maiumi; Keitelman, Irene; Coronel, Juan V; Amaral, María Marta; Rabadán, Alejandra T.; Salamone, Gabriela; Jancic, Carolina

doi:10.1007/s11060-021-03787-7

Cited by 10 publications

(28 citation statements)

References 45 publications

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“… 20–24 In a recent in vitro study, Vγ9Vδ2 T cells stimulated with (E)-4-hydroxy-3-methyl-but-enyl pyrophosphate were activated by glioblastoma cells and had cytotoxic effects. 24 In another recent preclinical study, stereotaxic administration of human Vγ9Vδ2 T cells in orthotopic glioma–bearing mice treated with zoledronic acid showed anti-tumor effects. 22 However, no one had yet determined which of the various possible ligands for γδ T cell receptors expressed in glioblastoma cells play an important role in γδ T cell cytotoxicity.…”

Section: Discussionmentioning

confidence: 97%

Human allogenic γδ T cells kill patient-derived glioblastoma cells expressing high levels of DNAM-1 ligands

et al. 2022

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Adoptive transfer of γδ T cells is a novel immunotherapeutic approach to glioblastoma. Few recent studies have shown the efficacy of γδ T cells against glioblastoma, but no previous studies have identified the ligand–receptor interactions between γδ T cells and glioblastoma cells. Here, we identify those ligand–receptor interactions and provide a basis for using γδ T cells to treat glioblastoma. Vγ9Vδ2 T cells were generated from peripheral blood mononuclear cells of healthy donors using artificial antigen presenting cells. MICA, ULBP, PVR and Nectin-2 expression in 10 patient-derived glioblastoma (PDG) cells were analyzed. The in vitro cytokine secretion from the γδ T cells and their cytotoxicity toward the PDG cells were also analyzed. The in vivo anti-tumor effects were evaluated using a U87 orthotopic xenograft glioblastoma model. Expression of ligands and cytotoxicity of the γδ T cells varied among the PDG cells. IFN-γ and Granzyme B secretion levels were significantly higher when γδ Tcells were co-cultured with high-susceptible PDG cells than when they were co-cultured with low-susceptible PDG cells. Cytotoxicity correlated significantly with the expression levels of DNAM-1 ligands of the PDG cells. Blocking DNAM-1 resulted in a decrease in γδ T cell–mediated cytotoxicity and cytokine secretion. Intratumoral injection of γδ T cells showed anti-tumor effects in an orthotopic mouse model. Allogenic γδ T cells showed potent anti-tumor effects on glioblastoma in a DNAM-1 axis dependent manner. Our findings will facilitate the development of clinical strategies using γδ T cells for glioblastoma treatment.

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Section: Discussionmentioning

confidence: 97%

Human allogenic γδ T cells kill patient-derived glioblastoma cells expressing high levels of DNAM-1 ligands

et al. 2022

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“…17,19,21 As observed in Figure 2, Vd2 + cells can differentiate into various functional subsets such as Th 1 , Th 2 , Th 17 or T reg -like cells, depending on the cytokines that are present within the TME. 19,26,[41][42][43][44] The anti-tumour role of cd T cells is relatively well-established due to the wide range of effector functions that they are known to carry out upon activation. cd T cells can act through both direct and indirect pathways to kill transformed cells, which has been demonstrated both in vitro and in vivo in multiple types of cancer.…”

Section: Role Of CD T Cells In Cancermentioning

confidence: 97%

“…Tumour progression and prognosis is largely dependent upon the type of infiltrating immune cells as well as the influence of the TME on activation or suppression of these cells. 17,19,20 cd T cells are a subset of T lymphocytes which constitute 1-10% of T cells in the peripheral blood of healthy adults and contribute to populations of tumour-infiltrating immune cells. 7 This subset of T cells expresses T-cell receptors (TCRs) that are composed of c and d chains, making them distinct from T cells expressing TCRs composed of a and b chains.…”

Section: T Cellsmentioning

confidence: 99%

“…The role of γδ T cells in cancer progression remains somewhat controversial due to the plasticity that these cells display. γδ T cells have been detected in many haematological and solid cancers where in some cases, higher levels of circulating and tumour‐infiltrating γδ T cells have been associated with better prognosis while in other cases, the opposite has been suggested 19 . Given that the primary source of pAgs in humans is via the mevalonate pathway, which is often upregulated in transformed cells, it is not surprising that Vδ2Vγ9 T cells are involved in cancer immunosurveillance 21,40 .…”

Section: γδ T Cellsmentioning

confidence: 99%

“…Vδ2Vγ9 T cells may be attracted to the TME via chemokines where they can detect transformed cells; however, few studies to date have investigated the specific receptors expressed by γδ T cells in relation to TME chemokines 8 . It is thought that the TME is a major factor in the polarisation of tumour‐infiltrating γδ T cells to a pro‐tumour phenotype, thus limiting their effectiveness as cytotoxic cells 17,19,21 . As observed in Figure 2, Vδ2 + cells can differentiate into various functional subsets such as Th 1 , Th 2 , Th 17 or T reg ‐like cells, depending on the cytokines that are present within the TME 19,26,41–44 …”

Section: γδ T Cellsmentioning

confidence: 99%

See 2 more Smart Citations

Effective γδ T‐cell clinical therapies: current limitations and future perspectives for cancer immunotherapy

Revesz,

Joyce,

Ebert

et al. 2024

Clin & Trans Imm

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Abstractγδ T cells are a unique subset of T lymphocytes, exhibiting features of both innate and adaptive immune cells and are involved with cancer immunosurveillance. They present an attractive alternative to conventional T cell‐based immunotherapy due, in large part, to their lack of major histocompatibility (MHC) restriction and ability to secrete high levels of cytokines with well‐known anti‐tumour functions. To date, clinical trials using γδ T cell‐based immunotherapy for a range of haematological and solid cancers have yielded limited success compared with in vitro studies. This inability to translate the efficacy of γδ T‐cell therapies from preclinical to clinical trials is attributed to a combination of several factors, e.g. γδ T‐cell agonists that are commonly used to stimulate populations of these cells have limited cellular uptake yet rely on intracellular mechanisms; administered γδ T cells display low levels of tumour‐infiltration; and there is a gap in the understanding of γδ T‐cell inhibitory receptors. This review explores the discrepancy between γδ T‐cell clinical and preclinical performance and offers viable avenues to overcome these obstacles. Using more direct γδ T‐cell agonists, encapsulating these agonists into lipid nanocarriers to improve their pharmacokinetic and pharmacodynamic profiles and the use of combination therapies to overcome checkpoint inhibition and T‐cell exhaustion are ways to bridge the gap between preclinical and clinical success. Given the ability to overcome these limitations, the development of a more targeted γδ T‐cell agonist‐checkpoint blockade combination therapy has the potential for success in clinical trials which has to date remained elusive.

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Relevance of Thymic Stromal Lymphopoietin on the Pathogenesis of Glioblastoma: Role of the Neutrophil

Infante Cruz,

Coronel,

Saibene Vélez

et al. 2024

Cell Mol Neurobiol

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Glioblastoma multiforme (GBM) is the most predominant and malignant primary brain tumor in adults. Thymic stromal lymphopoietin (TSLP), a cytokine primarily generated by activated epithelial cells, has recently garnered attention in cancer research. This study was aimed to elucidate the significance of TSLP in GBM cells and its interplay with the immune system, particularly focused on granulocyte neutrophils. Our results demonstrate that the tumor produces TSLP when stimulated with epidermal growth factor (EGF) in both the U251 cell line and the GBM biopsy (GBM-b). The relevance of the TSLP function was evaluated using a 3D spheroid model. Spheroids exhibited increased diameter, volume, and proliferation. In addition, TSLP promoted the generation of satellites surrounding the main spheroids and inhibited apoptosis in U251 treated with temozolomide (TMZ). Additionally, the co-culture of polymorphonuclear (PMN) cells from healthy donors with the U251 cell line in the presence of TSLP showed a reduction in apoptosis and an increase in IL-8 production. TSLP directly inhibited apoptosis in PMN from GBM patients (PMN-p). Interestingly, the vascular endothelial growth factor (VEGF) production was elevated in PMN-p compared with PMN from healthy donors. Under these conditions, TSLP also increased VEGF production, in PMN from healthy donors. Moreover, TSLP upregulated programed death-ligand 1 (PDL-1) expression in PMN cultured with U251. On the other hand, according to our results, the analysis of RNA-seq datasets from Illumina HiSeq 2000 sequencing platform performed with TIMER2.0 webserver demonstrated that the combination of TSLP with neutrophils decreases the survival of the patient. In conclusion, our results position TSLP as a possible new growth factor in GBM and indicate its modulation of the tumor microenvironment, particularly through its interaction with PMN. Graphical Abstract Protumoral activity of TSLP. Neutrophils (derived from GBM patients) and GBM cells (under EGF stimulus) not only produce TSLP but also express its receptor. TSLP induces PDL1 expression and decreases apoptosis on both GBM cells and neutrophils. TSLP also increases proliferation and satellite development on GBM cells, whereas favors more neutrophil infiltration by increasing IL8 production.

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Glioblastoma cells potentiate the induction of the Th1-like profile in phosphoantigen-stimulated γδ T lymphocytes

Cited by 10 publications

References 45 publications

Human allogenic γδ T cells kill patient-derived glioblastoma cells expressing high levels of DNAM-1 ligands

Human allogenic γδ T cells kill patient-derived glioblastoma cells expressing high levels of DNAM-1 ligands

Effective γδ T‐cell clinical therapies: current limitations and future perspectives for cancer immunotherapy

Relevance of Thymic Stromal Lymphopoietin on the Pathogenesis of Glioblastoma: Role of the Neutrophil

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