Defective γδ T-Cell Function and Granzyme B Gene Polymorphism in Newly Diagnosed Breast Care Patients. Expansion with Zoledronic Acid Partially Compensates for This Deficiency.

It has been well established that γδ T-cells play a role in innate anti-tumor immunity. However, the exact mechanism has not yet been fully elucidated. Most of these responses have been ascribed to Vγ9Vδ2 cells, which represent a major subset of the circulating γδ T-cells in humans (1–10%). IFN-γ and granzyme B are important molecules in the anti-tumor immune responses. Upon stimulation, γδ T-cells rapidly produce IFN-γ and cytotoxic molecules. In the present study we analyzed the immune responses by γδ T-cells in 30 newly diagnosed breast cancer patients and 30 normal controls before and after expansion with zoledronic acid. We also scanned the granzyme B gene polymorphism in breast cancer patients and controls. Our result revealed that γδ-T cells in PBMC were reduced in both frequency and function in breast cancer patients compared with the normal controls. Ex-vivo stimulation of γδ T-cells with zoledronic acid and IL-2 partially compensated for this deficiency, as it stimulates production of IFN- γ and release of cytotoxic molecules by these cells. However, the IFN- γ and granzyme B and cytotoxicity of the expanded γδ T-cells from breast cancer patients remained significantly below normal control. Genotypic analysis of granzyme B gene revealed significantly higher frequency of the RAH haplotype in breast cancer patients compared with normal controls. The prevalence of the wild genotype QPY/QPY was significantly higher in normal controls compared with the breast cancer patients. Cytotoxicity by γδ T-cells against various targets was reduced in breast cancer patients compared to normal controls. In conclusion, our analysis shows a defective immune function of γδ T-cells and granzyme B gene polymorphism in breast cancer patients. The γδ T-cell function defect in these patients can be partially corrected by zoledronic acid. Further studies of γδ T-cell function and granzyme B gene polymorphism in other cancers, as well as the therapeutic use of zoldedronic acid is warranted.