Defective gammadelta T-cell function and granzyme B gene polymorphism in a cohort of newly diagnosed breast cancer patients

Exp Hematol. 2009 Jul;37(7):838-48. doi: 10.1016/j.exphem.2009.04.003. Epub 2009 May 14.


Objective: The purpose of this study was to examine the antitumor immune function of gammadelta T cells and to scan the granzyme B gene for the known single nucleotide polymorphism in breast cancer patients and normal controls.

Materials and methods: Levels, cytotoxicity, and functional capacity of gammadelta T cells in peripheral blood mononuclear cells were assessed by flow cytometry, (51)Cr release, and ELISpot assays, respectively. Furthermore, sequence based typing was adopted to screen for granzyme B gene polymorphism.

Results: We have found that the frequency and function of gammadelta T cells are reduced both in peripheral blood mononuclear cells of 30 newly diagnosed breast cancer patients (2 [1.2, 3]), compared with 38 normal controls (3.2 [2.5, 5.7]) (p=0.02). In addition, resting gammadelta T cells from breast cancer patients produced significantly more interleukin-6 and tumor necrosis factor-alpha than normal controls. Moreover, ex vivo stimulation of gammadelta T cells with zoledronic acid and interleukin-2 compensated in part for this deficiency, as it stimulated the proliferation, cytokine production, and enhanced the expression of messenger RNA of granzyme B. Interestingly, when the known granzyme B gene polymorphism was screened, we found the prevalence of the mutated genotype RAH/RAH to be significantly (p<0.017) associated with breast cancer patients (14.30%) compared with normal donors (1.40%). Cytotoxicity exerted by gammadelta T cells on Daudi and MCF-7 was significantly higher in donors with the wild-type QPY/QPY (50%) compared with donors with RAH/RAH (21%).

Conclusions: Our data suggest that reduction in the proportion of gammadelta T cells and granzyme B gene polymorphism leads to defective immune function in breast cancer patients. Treatment with zoledronic acid amend partially this fault. Further studies of gammadelta T cells function and granzyme B gene polymorphism in cancers, as well as the potential therapeutic use of zoledronic acid are warranted.

MeSH terms

  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Case-Control Studies
  • Cell Line, Tumor
  • Cohort Studies
  • Cytotoxicity, Immunologic
  • Diphosphonates / pharmacology
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Granzymes / genetics*
  • Humans
  • Imidazoles / pharmacology
  • Immunophenotyping
  • Interleukin-6 / biosynthesis
  • Polymerase Chain Reaction
  • Polymorphism, Genetic*
  • Receptors, Antigen, T-Cell, gamma-delta / immunology
  • Receptors, Antigen, T-Cell, gamma-delta / physiology*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Zoledronic Acid


  • Diphosphonates
  • Imidazoles
  • Interleukin-6
  • Receptors, Antigen, T-Cell, gamma-delta
  • Tumor Necrosis Factor-alpha
  • Zoledronic Acid
  • Granzymes