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

Gaafar, Ameera; Aljurf, Mahmoud Deeb; Al-Sulaiman, Abdullah; Iqniebi, Alia; Manogaran, Pulicat S.; Mohamed, Gamal Eldin H.; Al-Sayed, Adher; Alzahrani, Hazaa; Alsharif, Fahad; Mohareb, Fahad; Ajarim, Dahish; Tabakhi, Abdelghani; Al-Hussein, Khalid

doi:10.1016/j.exphem.2009.04.003

« Previous Next »Experimental Hematology
Volume 37, Issue 7 , Pages 838-848, July 2009

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

Ameera Gaafar
- Histocompatibility and Immunogenetics, Riyadh, Saudi Arabia
Mahmoud Deeb Aljurf
- King Faisal Cancer Center, Riyadh, Saudi Arabia
Abdullah Al-Sulaiman
- Histocompatibility and Immunogenetics, Riyadh, Saudi Arabia
Alia Iqniebi
- Histocompatibility and Immunogenetics, Riyadh, Saudi Arabia
Pulicat S. Manogaran
- Flow Cytometry, Stem Cell Therapy Program, Riyadh, Saudi Arabia
Gamal Eldin H. Mohamed
- Department of Biostatistics, Epidemiology, and Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Adher Al-Sayed
- King Faisal Cancer Center, Riyadh, Saudi Arabia
Hazaa Alzahrani
- King Faisal Cancer Center, Riyadh, Saudi Arabia
Fahad Alsharif
- King Faisal Cancer Center, Riyadh, Saudi Arabia
Fahad Mohareb
- King Faisal Cancer Center, Riyadh, Saudi Arabia
Dahish Ajarim
- King Faisal Cancer Center, Riyadh, Saudi Arabia
Abdelghani Tabakhi
- Department of Pathology and Laboratory Medicine, Riyadh, Saudi Arabia
Khalid Al-Hussein
- Histocompatibility and Immunogenetics, Riyadh, Saudi Arabia
- Offprint requests to: Khaled Al-Hussein, Ph.D., Histocompatibility and Immunogenetics Research Unit, Stem Cell Therapy Program, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia

Received 26 March 2008; received in revised form 9 March 2009; accepted 14 April 2009. published online 22 April 2009.

Objective

The purpose of this study was to examine the antitumor immune function of γδ 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 γδ T cells in peripheral blood mononuclear cells were assessed by flow cytometry, ⁵¹Cr 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 γδ 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 γδ T cells from breast cancer patients produced significantly more interleukin-6 and tumor necrosis factor−α than normal controls. Moreover, ex vivo stimulation of γδ 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 γδ 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 γδ 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 γδ T cells function and granzyme B gene polymorphism in cancers, as well as the potential therapeutic use of zoledronic acid are warranted.