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


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.
Gaafar
Ameera
A
Histocompatibility and Immunogenetics, Riyadh, Saudi Arabia.
Aljurf
Mahmoud Deeb
MD
Al-Sulaiman
Abdullah
A
Iqniebi
Alia
A
Manogaran
Pulicat S
PS
Mohamed
Gamal Eldin H
GE
Al-Sayed
Adher
A
Alzahrani
Hazaa
H
Alsharif
Fahad
F
Mohareb
Fahad
F
Ajarim
Dahish
D
Tabakhi
Abdelghani
A
Al-Hussein
Khalid
K
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D015331:Cohort Studies; D003602:Cytotoxicity, Immunologic; D004164:Diphosphonates / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D053804:Granzymes / Q000235:genetics*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016130:Immunophenotyping; D015850:Interleukin-6 / Q000096:biosynthesis; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000077211:Zoledronic Acid
D004164:Diphosphonates; D007093:Imidazoles; D015850:Interleukin-6; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014409:Tumor Necrosis Factor-alpha; D000077211:Zoledronic Acid; D053804:Granzymes