Aminobisphosphonate-activated γδ T cells in immunotherapy of cancer: doubts no more

Caccamo, Nadia; Meraviglia, Serena; Scarpa, Francesco; Mendola, Carmela La; Santini, Daniele; Bonanno, Cesira T.; Misiano, Gabriella; Dieli, Francesco; Salerno, Alfredo

doi:10.1517/14712598.8.7.875

Cited by 45 publications

(27 citation statements)

References 49 publications

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“…This would have consequences for tissue renewal, repair, and wound healing where apoptotic or necrotic cells need to be removed in a controlled, noninflammatory fashion. Additionally and importantly, ␥␦ T cells are well known to take an active part in antitumor immune responses, and their use in immunotherapeutic cancer treatments is part of several clinical trials (41,42). Strid et al (43) recently showed that murine intraepithelial ␥␦ T cells respond to and inhibit carcinogenesis in response to specific molecular signals and Peng et al demonstrated that ␥␦ T cells within cancer tissue can operate as T regulatory cells suppressing an antitumor response (39).…”

Section: Discussionmentioning

confidence: 99%

Human γδ T Cells: A Lymphoid Lineage Cell Capable of Professional Phagocytosis

Wong

et al. 2009

The Journal of Immunology

132

110

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Professional phagocytosis in mammals is considered to be performed exclusively by myeloid cell types. In this study, we demonstrate, for the first time, that a mammalian lymphocyte subset can operate as a professional phagocyte. By using confocal microscopy, transmission electron microscopy, and functional Ag presentation assays, we find that freshly isolated human peripheral blood γδ T cells can phagocytose Escherichia coli and 1 μm synthetic beads via Ab opsonization and CD16 (FcγRIII), leading to Ag processing and presentation on MHC class II. In contrast, other CD16+ lymphocytes, i.e., CD16+/CD56+ NK cells, were not capable of such functions. These findings of distinct myeloid characteristics in γδ T cells strongly support the suggestion that γδ T cells are evolutionarily ancient lymphocytes and have implications for our understanding of their role in transitional immunity and the control of infectious diseases and cancer.

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Section: Discussionmentioning

confidence: 99%

Human γδ T Cells: A Lymphoid Lineage Cell Capable of Professional Phagocytosis

Wong

et al. 2009

The Journal of Immunology

132

110

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Section: Like Other 'Unconventional' T Cells Carrying An Ab Tcr Such mentioning

confidence: 99%

“…Administration of Vc9/Vd2 T cell stimulating agents and the adoptive transfer of ex vivo expanded Vc9/Vd2 T cell have proven to be safe in patients [19][20][21]. The promising role of Vc9/Vd2 T cells as cytotoxic effectors against a range of solid and hematological malignancies notwithstanding, there are no detailed reports on anti-tumor ab T cell or antibody responses in treated individuals.…”

Section: Innate Regulation Of Adaptive Immune Responses: Vd2 + Versusmentioning

confidence: 99%

“…Overproduction of the low bioactivity compounds IPP and DMAPP as a result of a dysregulation of the mevalonate pathway in human cells, be it in metabolically active tissues including tumor cells or through inhibition of farnesyl pyrophosphate synthase by aminobisphophonates such as zoledronate, is thought to render such cells targets of Vc9/Vd2 T cells, despite the absence of the high bioactivity metabolite HMB-PP in this context [11,[16][17][18]. Zoledronate and related drugs are therefore receiving substantial attention as Vc9/Vd2 T cellstimulating agents in vivo especially with respect to immunotherapies against advanced solid and hematological tumors [19][20][21].The recent landmark discovery of butyrophilin 3A (BTN3A/ CD277) as the long-sought unconventional 'presenting' molecule for HMB-PP and IPP provided a molecular mechanism that elegantly integrates the action of endogenous and exogenous stimuli via binding of phosphoantigens to the intracellular B30.2 (PRY-SPRY) domain of BTN3A [22][23][24][25]. This intracellular recognition of HMB-PP and IPP evokes similar cases of B30.2-mediated innate responses through proteins such as TRIM5a and TRIM21 [26,27], thereby adding BTN3A to the rapidly growing number of innate pattern recognition receptors.…”

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confidence: 99%

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

Tyler

Doherty

Moser

et al. 2015

Cellular Immunology

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a b s t r a c tUnconventional T cells are gaining center stage as important effector and regulatory cells that orchestrate innate and adaptive immune responses. Human Vc9/Vd2 T cells are amongst the best understood unconventional T cells, as they are easily accessible in peripheral blood, can readily be expanded and manipulated in vitro, respond to microbial infections in vivo and can be exploited for novel tumor immunotherapies. We here review findings that suggest that Vc9/Vd2 T cells, and possibly other unconventional human T cells, play an important role in bridging innate and adaptive immunity by promoting the activation and differentiation of various types of antigen-presenting cells (APCs) and even turning into APCs themselves, and thereby pave the way for antigen-specific effector responses and long-term immunological memory. Although the direct physiological relevance for most of these mechanisms still needs to be demonstrated in vivo, these findings may have implications for novel therapies, diagnostic tests and vaccines.Ó 2015 Published by Elsevier Inc. Introduction cd T cells represent a third lineage of lymphocytes expressingre-arranged antigen receptors that co-evolved with 'classical' B cells and ab T cells over 400 million years, arguing for a crucial and non-redundant contribution of each lymphocyte to effective immune responses, and hence the evolutionary survival of all jawed vertebrate species [1]. 30 years have passed since the accidental and unexpected cloning of the cd T cell receptor (TCR) and the subsequent realization that ab T cells and cd T cells are fundamentally different with respect to the types of antigens they recognize and the distinct effector functions triggered upon such recognition. However, the manifold contributions of cd T cells to homeostasis, inflammation, infection and tumor surveillance have historically been neglected and are only beginning to be integrated into comprehensive models of the immune system [1][2][3][4][5][6][7].1. Innate-like pattern recognition by human Vc9/Vd2 T cells Like other 'unconventional' T cells carrying an ab TCR such as mucosal-associated invariant T (MAIT) cells and natural killer T (NKT) cells, cd T cells are characterized by a markedly restrictedTCR usage that allows them to recognize self and non-self molecules in the absence of classical antigen presentation via MHC I or MHC II. Vc9/Vd2 + cd T cells represent the major cd T cell subset in human peripheral blood where they typically comprise 1-5% in healthy adults [8]. In many microbial infections, Vc9/Vd2 T cells increase locally and/or systemically [9,10] and can reach in excess of 50% of all peripheral T cells within a matter of days [11], revealing a fundamental role of this unconventional T cell population in acute disease and suggesting their exploitation for diagnostic and therapeutic purposes [12][13][14]. Vc9/Vd2 T cells uniformly respond to a class of low molecular weight molecules often referred to as 'phosphoantigens' that represent metabolites of the isoprenoid biosynthesis...

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“…Questo meccanismo spiega anche perchè l'intensità e la frequenza della reazione di fase acuta sia in qualche modo in relazione con la potenza dei diversi aminobisfosfonati. Questo effetto, riportato come un avvento avverso, rappresenta in realtà il segnale della stimolazione di una sottopopolazione linfocitaria che oggi viene valorizzata nel trattamento di soggetti neoplastici, come un ulteriore meccanismo antineoplastico indiretto di acido zoledronico (27). Una caratteristica tipica della reazione di fase acuta legata agli amino-bisfosfonati è che l'incidenza del disturbo si riduce significativamente dopo la prima somministrazione.…”

Section: La Reazione DI Fase Acutaunclassified

Evidences of safety and tolerability of the zoledronic acid 5 mg yearly in the post-menopausal osteoporosis: the HORIZON project

Carbonare¹,

Bertoldo²,

Cascio³

2011

Reumatismo

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di trattamento. Pertanto il profilo di efficacia e sicurezza sono elementi fondamentali per la registrazione di ogni nuovo trattamento per la riduzione della fragilità scheletrica e per garantire una buona adesione alla terapia. La valutazione dell'efficacia e della sicurezza si basa essenzialmente sui risultati ottenuti nei grandi studi clinici multicentrici, ma ogni nuova molecola viene anche valutata in studi istologici rivolti a valutare l'effettivo impatto dei farmaci sul rimodellamento e sulla struttura dell'osso. INTRODUZIONE L'osteoporosi postmenopausale è una condizione cronica che richiede prolungati periodi Reumatismo, 2009; 61(1):54-64

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Aminobisphosphonate-activated γδ T cells in immunotherapy of cancer: doubts no more

Cited by 45 publications

References 49 publications

Human γδ T Cells: A Lymphoid Lineage Cell Capable of Professional Phagocytosis

Human γδ T Cells: A Lymphoid Lineage Cell Capable of Professional Phagocytosis

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

Evidences of safety and tolerability of the zoledronic acid 5 mg yearly in the post-menopausal osteoporosis: the HORIZON project

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