nach oben

Erschienen in:

01.01.2009 | Original Article

In vivo effects of zoledronic acid on peripheral γδ T lymphocytes in early breast cancer patients

verfasst von: Daniele Santini, Federico Martini, Maria Elisabetta Fratto, Sara Galluzzo, Bruno Vincenzi, Chiara Agrati, Federica Turchi, Paola Piacentini, Laura Rocci, John S. Manavalan, Giuseppe Tonini, Fabrizio Poccia

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 1/2009

Einloggen, um Zugang zu erhalten

Abstract

Introduction

Amino-bisphosphonates are potent activators of human γδ T cells. The aim of our study was to evaluate the immunomodulating properties of a single-dose of zoledronic acid (ZA) on γδ T cells in a select group of disease-free breast cancer patients with osteopenia.

Materials and methods

Blood samples were obtained, from 23 patients, before and 7, 28, 56, 90 and 180 days after a single-dose (4 mg) of ZA and analyzed by flow cyometry.

Results

A significant decrease of the different γδ T cell subsets was observed: Naïve (CD3+/Vdelta2+/CD45RA+/CD27+) after 180 days (P < 0.01); Central Memory (CD3+/Vdelta2+/CD45RA-CD27+) after 28 (P < 0.05), 90 (P < 0.01) and 180 days (P < 0.01); and Effector Memory (CD3+/Vdelta2+/CD45RA-/CD27-) after 56 (P < 0.01) and 90 (P < 0.05) days. Based on the observed γδ T cells kinetics patients could be divided in two groups: “responders” that showed a significant decrease in total numbers of γδ T cells and “non-responders” that showed no significant change. However, in vitro phosphoantigen stimulation of patients cells did not show significant differences in terms of IFN-γ response by Vδ2 T cells.

Conclusion

We describe for the first time a long-lasting activation of effector subsets of γδ T cells in disease-free breast cancer patients after a single-dose of ZA. Our results highlight the need to further investigate the clinical significance of the immunomodulating properties of N-BPs.

Green JR, Muller K, Jaeggi KA (1994) Preclinical pharmacology of CGP 42′446, a new, potent, heterocyclic bisphosphonate compound. J Bone Miner Res 9:745–751PubMedCrossRef

Sietsema WK, Ebetino FH, Salvagno AM, Bevan JA (1989) Antiresorptive dose–response relationship across three generations of bisphosphonates. Drugs Exp Clin Res 15:389–396PubMed

Hillner BE, Ingle JN, Chlebowski RT, Gralow J, Yee GC, Janjan NA, Cauley JA et al (2004) American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 22:1351CrossRef

Saad F, Gleason D, Murray R et al (2003) Zoledronic acid is well tolerated for up to 24 months and significantly reduces skeletal complications in patients with advanced prostate cancer metastatic to bone. J Urol 169(suppl):394

Rosen LS, Gordon D, Tchekmedyian NS, Yanagihara R, Hirsh V, Krzakowski M, Pawlicki M et al (2004) Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with non small cell lung carcinoma and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial. Cancer 100:2613–2621PubMedCrossRef

Van Beek E, Pieterman E, Cohen L, Lowick C, Papapoulous S (1999) Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biochem Biophys Res Commun 264:108–111PubMedCrossRef

Zhang FL, Casey PJ (1996) Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem 65:241–269PubMedCrossRef

Santini D, Vespasiani Gentilucci U, Vincenzi B, Picardi A, Vasaturo F, LaCesa A, Onori N et al (2003) The antineoplastic role of bisphosphonates: from basic research to clinical evidence. Ann Oncol 14:1468–1476PubMedCrossRef

Kabelitz D, Marischen L, Oberg HH, Holtmeier W, Wesch D (2005) Epithelial defence by γ/δ T cells. Int Arch Allergy Immunol 137:73–81PubMedCrossRef

10.

Hiraga T, Williams PJ, Ueda A, Tamura D, Yoneda D (2004) Zoledronic acid inhibits visceral metastasis in the 4T1/luc mouse breast cancer model. Clin Cancer Res 10:4554–4567CrossRef

11.

Caccamo N, Meraviglia S, Ferlazzo V, Angelini D, Borsellino G, Poccia F, Battistini L et al (2005) Differential requirements for antigen or homeostatic cytokines for proliferation and differentiation of human Vgamma9Vdelta2 naïve, memory and effector T cell subsets. Eur J Immunol 35:1764–1772PubMedCrossRef

12.

Zocchi MR, Ferrarini M, Rugarli C (1990) Selective lysis of the autologous tumor by delta TCS1+ gamma/delta+ tumor-infiltrating lymphocytes from human lung carcinomas. Eur J Immunol 20:2685–2689PubMedCrossRef

13.

Choudhary A, Davodeau F, Moreau A, Peyrat MA, Bonneville M, Jotereau F (1995) Selective lysis of autologous tumor cells by recurrent gamma delta tumor-infiltrating lymphocytes from renal carcinoma. J Immunol 154:3932–3940PubMed

14.

Zhao X, Wei YQ, Kariya Y, Teshigawara K, Uchida A (1995) Accumulation of gamma/delta T cells in human dysgerminoma and seminoma: roles in autologous tumor killing and granuloma formation. Immunol Invest 24:607–618PubMedCrossRef

15.

Bagot M, Heslan M, Dubertret L, Roujeau JC, Tourine R, Levy JP (1985) Antigen-presenting properties of human epidermal cells compared with peripheral blood mononuclear cells. Br J Dermatol 113(suppl 28):55PubMedCrossRef

16.

Laad AD, Thomas ML, Fakih AR, Chiplunkar SV (1990) Human gamma delta T cells recognize heat shock protein-60 on oral tumor cells. Int J Cancer 80:709–714CrossRef

17.

Fisch P, Malkovsky M, Kovats S, Sturm E, Braakman E, Klein BS, Voss SD et al (1990) Recognition by human Vγ9/Vδ2 T cells of a GroEL homolog on Daudi Burkitt’s lymphoma cells. Science 250:1269–1273PubMedCrossRef

18.

Freedman MS, D’Souza S, Antel JP (1997) Gamma delta T-cell-human glial cell interactions In vitro induction of gamma-delta T-cell expansion by human glial cells. J Neuroimmunol 74:135–142PubMedCrossRef

19.

Suzuki Y, Fujimiya Y, Ohno T, Katakura R, Yoshimoto T (1999) Enhancing effect of tumor necrosis factor (TNF)-alpha, but not IFN-gamma, on the tumor-specific cytotoxicity of gammadelta T cells from glioblastoma patients. Cancer Lett 140:161–167PubMedCrossRef

20.

Schilbach KE, Geiselhart A, Wessels JT, Niethammer D, Handgretinger R (2000) Human gammadelta T lymphocytes exert natural and IL-2-induced cytotoxicity to neuroblastoma cells. J Immunother 23:536–548PubMedCrossRef

21.

Courvasier M, Moureau-Aubry A, Diez E, Bennouna J, Mosnier JF, Scotet E, Bonneville M et al (2005) Vγ9/Vδ2 T cell response to colon carcinoma cells. J Immunol 175(8):5481–5488

22.

Ferrarini M, Ferrero E, Dagna L, Poggi A, Zocchi MR (2002) Human gammadelta T cells: a nonredundant system in the immune surveillance against cancer. Trends Immunol 23:14–18PubMedCrossRef

23.

Kunzmann V, Bauer E, Feurle J, Weissinger F, Tony HP, Wilhelm M (2000) Stimulation of γδ T cells by aminobisphosphonates and induction of antiplasmacell activity in multiple myeloma. Blood 96:384–392PubMed

24.

Kunzmann V, Bauer E, Wilhelm M (1999) γδ T cell stimulation by pamidronate. N Engl J Med 340:737–738PubMedCrossRef

25.

Dieli F, Gebbia N, Poccia F, Caccamo N, Montesano C, Fulfaro F, Arcara C et al (2003) Induction of gammadelta T-lymphocyte effector functions by bisphosphonate zoledronic acid in cancer patients in vivo. Blood 102:2310–1PubMedCrossRef

26.

Ferlazzo V, Sferrazza C, Caccamo N, Di Fede G, Di Lorenzo G, D’Asaro M, Meraviglia S et al (2006) In vitro effects of aminobisphosphonates on Vgamma9Vdelta2 T cell activation and differentiation. Int J Immunopathol Pharmacol 19:309–317PubMed

27.

Dieli F, Poccia F, Lipp M, Sireci G, Caccamo N, Di Sano C, Salerno A (2003) Differentiation of effector/Memory Vdelta2 T cells and migratory routes in lymph nodes or inflammatory sites. J Exp Med 198:391–397PubMedCrossRef

28.

Galluzzo S, Santini D, Vincenzi B, Caccamo N, Meraviglia F, Salerno A, Dieli F et al (2007) Immunomodulating role of bisphosphonates on human gamma delta T cells: an intriguing and promising aspect of their antitumour activity. Expert Opin Ther Targets 11(7):941–954PubMedCrossRef

29.

Gober HJ, Kistowska M, Angman L, Jeno P, Mori L, De Libero G (2003) Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells. J Exp Med 197:163–168PubMedCrossRef

30.

Watanabe N, Narita M, Yokoyama A, Sekiguchi A, Saito A, Tochiki N, Furukawa T et al (2006) Type I IFN-mediated enhancement of anti-leukemic cytotoxicity of gammadelta T cells expanded from peripheral blood cells by stimulation with zoledronate. Cytotherapy 8:118–129PubMedCrossRef

31.

Thompson K, Rogers MJ (2004) Statins prevent bisphosphonate-induced gamma, delta-T-cell proliferation and activation in vitro. J Bone Miner Res 19(2):278–288PubMedCrossRef

32.

Rogers MJ (2003) New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des 9(32):2643–2658PubMedCrossRef

Titel: In vivo effects of zoledronic acid on peripheral γδ T lymphocytes in early breast cancer patients
verfasst von: Daniele Santini
Federico Martini
Maria Elisabetta Fratto
Sara Galluzzo
Bruno Vincenzi
Chiara Agrati
Federica Turchi
Paola Piacentini
Laura Rocci
John S. Manavalan
Giuseppe Tonini
Fabrizio Poccia
Publikationsdatum: 01.01.2009
Verlag: Springer-Verlag
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 1/2009
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-008-0521-6

Neu im Fachgebiet Onkologie

19.04.2024 | EAU 2024 | Kongressbericht | Nachrichten

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

In vivo effects of zoledronic acid on peripheral γδ T lymphocytes in early breast cancer patients

Abstract

Introduction

Materials and methods

Results

Conclusion

Neu im Fachgebiet Onkologie

Prostatakarzinom: EU initiiert neues Screeningkonzept

Blasenkarzinom – Biomarker statt Zytologie?

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Adjuvante Brustkrebstherapie: Doppelt hält besser

Update Onkologie

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Abstract

Introduction

Materials and methods

Results

Conclusion

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 1/2009

Efficiency of adjuvant active specific immunization with Newcastle disease virus modified tumor cells in colorectal cancer patients following resection of liver metastases: results of a prospective randomized trial

Expression and function of T cell homing molecules in Hodgkin’s lymphoma

Systemic immune effects of adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide and/or radiotherapy in breast cancer: a longitudinal study

Regulation of antigen presentation machinery in human dendritic cells by recombinant adenovirus

IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism

Vaccine-specific local T cell reactivity in immunotherapy-associated vitiligo in melanoma patients

Neu im Fachgebiet Onkologie

Prostatakarzinom: EU initiiert neues Screeningkonzept

Blasenkarzinom – Biomarker statt Zytologie?

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Adjuvante Brustkrebstherapie: Doppelt hält besser

Update Onkologie