Dysfunctional Vγ9Vδ2 T cells are negative prognosticators and markers of dysregulated mevalonate pathway activity in chronic lymphocytic leukemia cells

Coscia, Marta; Vitale, Candida; Peola, Silvia; Foglietta, Myriam; Rigoni, Micol Maria; Griggio, Valentina; Castella, Barbara; Angelini, Daniela F.; Chiaretti, Sabina; Riganti, Chiara; Guarini, Anna; Drandi, Daniela; Ladetto, Marco; Bosìa, Amalia; Foà, Robin; Battistini, Luca; Boccadoro, Mario; Fournié, Jean Jacques; Massaia, Massimo

doi:10.1182/blood-2012-03-417519

Cited by 54 publications

(78 citation statements)

References 31 publications

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“…Multidimensional scaling analysis as a robust analytical tool helped us to identify specific T‐cell populations that may be of biological significance in CLL progression. Although many previous studies have established a prognostic role for individual T‐cell subpopulations, such as Treg or gamma‐delta T‐cells, it was not surprising that our global T‐cell profile correlated with disease progression independently of established prognostic factors such as cytogenetics or immunoglobulin mutational status. Yet, our analysis evidently shows that no single event or cell type holds all the information necessary to describe T‐cell‐induced progression in CLL.…”

Section: Discussionmentioning

confidence: 82%

Multidimensional scaling analysis identifies pathological and prognostically relevant profiles of circulating T‐cells in chronic lymphocytic leukemia

Rissiek

Schulze

Bacher

et al. 2014

Intl Journal of Cancer

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Antitumor immunity in chronic lymphocytic leukemia (CLL) is hampered by highly dysfunctional T-cells. Although certain T-cell subsets have been reported to be of prognostic significance in this disease, their interplay is complex and it remains incompletely understood which of these subsets significantly drive CLL progression. Here, we determined immunological profiles of 24 circulating T-cell subsets from 79 untreated individuals by multiparametric flow cytometry. This screening cohort included healthy donors, patients with monoclonal B-cell lymphocytosis (MBL), Rai 0 CLL and advanced CLL. We applied multidimensional scaling analysis as rigorous and unbiased statistical tool to globally assess the composition of the circulating T-cell environment and to generate T-cell scores reflecting its integrity. These scores allowed clear distinction between advanced CLL and healthy controls, whereas both MBL and Rai 0 CLL showed intermediate scores mirroring the biological continuum of CLL and its precursor stages. T-cell stimulation and suppression assays as well as longitudinal T-cell profiling showed an increasingly suppressive regulatory function initiating at the MBL stage. Effector function was impaired only after transition to CLL and partially recovered after chemoimmunotherapy. In an independent validation cohort of 52 untreated CLL cases, aberrant T-cell profiles were significantly associated with shorter time to treatment independently of other prognostic parameters. Random forest modeling predicted regulatory T-cell, gamma/delta and NKT-cells, as well as exhaustion of the CD81 subset as potential drivers of progression. Our data illustrate a pathological T-cell environment in MBL that evolves toward a more and more suppressive and prognostically relevant profile across the disease stages.

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Section: Discussionmentioning

confidence: 82%

Multidimensional scaling analysis identifies pathological and prognostically relevant profiles of circulating T‐cells in chronic lymphocytic leukemia

Rissiek

Schulze

Bacher

et al. 2014

Intl Journal of Cancer

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“…10 The anti-leukemic effect of TCR agonists was supported by a trial showing partial remission in two AML patients receiving N-BP with IL-2. 13 As Vg9Vd2 T cells are altered in patients, 12,14 the adoptive transfer of these cells emerges as a promising alternative. 15 However, 50% of N-BP-treated blasts still failed to enhance allogeneic gd T cells cytotoxicity in vitro, suggesting that novel-triggering agents are still warranted.…”

Section: Introductionmentioning

confidence: 99%

BTN3A molecules considerably improve Vγ9Vδ2T cells-based immunotherapy in acute myeloid leukemia

et al. 2016

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Given their recognized ability to kill acute myeloid leukemia (AML) blasts both in vitro and in vivo, Vg9Vd2 T cells are of growing interest in the design of new strategies of immunotherapy. We show that the Butyrophilin3A (BTN3A, CD277) subfamily is a critical determinant of Vg9Vd2 TCR-mediated recognition of human primary AML blasts ex vivo. Moreover, anti-BTN3A 20.1 agonist monoclonal antibodies (mAbs) can trigger BTN3A on AML blasts leading to further enhanced Vg9Vd2 T cell-mediated killing, but this mAb had no enhancing effect upon NK cell-mediated killing. We show that monocytic differentiation of primary AML blasts accounts for their AminoBisphosphonate (N-BP)-mediated sensitization to Vg9Vd2 T cells. In addition, anti-BTN3A 20.1 mAbs could specifically sensitize resistant blasts to Vg9Vd2 T cells lysis and overcome the poor effect of N-BP treatment on those blasts. We confirmed the enhancement of Vg9Vd2 T cells activity by anti-BTN3A 20.1 mAb using a human AML xenotransplantation mouse model. We showed that anti-BTN3A 20.1 mAb combined with Vg9Vd2 T cells immunotherapy could increase animal survival and decrease the leukemic burden in blood and bone marrow. These findings could be of great interest in the design of new immunotherapeutic strategies for treating AML.

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“…Moreover, poor proliferative response of Vg9Vd2 T cells to zoledronate in vitro was found to be a negative prognostic indicator in chronic lymphocytic leukemia (24).…”

mentioning

confidence: 99%

“…Among N-BP-expanded gd T cells, effector/memory-like T cells (T EMs , CD45RA 2 CD27 2 ) predominate (23) and, in patients with certain hematologic malignancies, poor proliferative response to zoledronate, which is the most potent N-BP available for clinical use, correlated with an even more pronounced bias toward T EM and terminally differentiated effector memory T cells re-expressing CD45RA (T EMRA , CD45RA + CD27 2 ) (24).…”

mentioning

confidence: 99%

Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

Nussbaumer

Gruenbacher

Gander

et al. 2013

The Journal of Immunology

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The potent nitrogen-containing bisphosphonate zoledronate inhibits farnesyl pyrophosphate synthase, a key enzyme of the mevalonate pathway that is often hyperactive in malignant cells. Zoledronate activates human Vγ9Vδ2 T cells, which are immune sentinels of cell stress and tumors, through upstream accumulation of the cognate Ag isopentenyl pyrophosphate. IL-18 was shown to enhance zoledronate-induced γδ T cell activation. Although monocytes have been considered important accessory cells that provide the Ag isopentenyl pyrophosphate, CD56brightCD11c+ NK cells were postulated to mediate the costimulatory effects of IL-18. We report in this article that downstream depletion of geranylgeranyl pyrophosphate (GGPP), which is required for protein prenylation, caused cell stress in monocytes, followed by caspase-1–mediated maturation and release of IL-18, which, in turn, induced γδ T cell CCL2. Likewise, zoledronate caused a substantial delay in γδ T cell expansion, which could be skipped by GGPP supplementation. Moreover, repletion of GGPP, which prevented acute zoledronate toxicity, and supplementation with IL-18, which strongly upregulated IL-2Rα (CD25) and favored the central memory phenotype, were sufficient to enable zoledronate-induced expansion of highly purified γδ T cells, even when starting cell numbers were as low as 104 γδ T cells. Our study reveals essential components of γδ T cell activation and indicates that exogenous IL-18, which can directly costimulate γδ T cells, eliminates the need for any accessory cells. Our findings will facilitate the generation of robust γδ T cells from small blood or tissue samples for cancer immunotherapy and immune-monitoring purposes.

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Dysfunctional Vγ9Vδ2 T cells are negative prognosticators and markers of dysregulated mevalonate pathway activity in chronic lymphocytic leukemia cells

Cited by 54 publications

References 31 publications

Multidimensional scaling analysis identifies pathological and prognostically relevant profiles of circulating T‐cells in chronic lymphocytic leukemia

Multidimensional scaling analysis identifies pathological and prognostically relevant profiles of circulating T‐cells in chronic lymphocytic leukemia

BTN3A molecules considerably improve Vγ9Vδ2T cells-based immunotherapy in acute myeloid leukemia

Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

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