Zoledronate Stimulates γδ T Cells in Prostate Cancer Patients

Abstract

Androgen deprivation therapy is the mainstay of treatment for prostate cancer. Given its frequent failure, new therapy that reduces prostate cancer progression would be a breakthrough in treating this disease. Bisphosphonates are well-established agents for treating skeletal-related events (SREs) in prostate cancer patients with bone metastases. Exposure to bisphosphonates may not only reduce the incidence of SREs, but also have anticancer effects by modulating a patient's immunity. The purpose of this study was to examine the effect of zoledronate (ZOL) on gamma delta T cells, serum prostate-specific antigen (PSA) levels, and velocities. The effect of ZOL, with and without IL-2, on gamma delta T cell activation was examined in vitro. Furthermore, the activated state and the number of gamma delta T cells and changes in serum PSA levels were examined for patients who received ZOL infusion for the prevention of SREs. We found that ZOL activated gamma delta T cells, and the number of gamma delta T cell was increased when IL-2 was administered with ZOL in vitro. Comparisons before and after the first ZOL infusion revealed that gamma delta T cells in peripheral blood were activated by ZOL. Moreover, after the first ZOL treatment, reduction in serum PSA was observed in 3 of 11 patients, and reduction in PSA velocity was observed in 5 of 10 patients. Our findings indicate that ZOL stimulates gamma delta T cells in vivo and in vitro. This study provides further insight into the ability of gamma delta T cells to induce an antitumor immune response.

Empowering gamma delta T cells with antitumor immunity by dendritic cell-based immunotherapy

“…1). Given the fact that the presence of activated gd T cells in cancer patients is associated with a beneficial outcome 16,[22][23][24] , monitoring gd T cells would be an interesting parameter for evaluation of DC vaccines.…”

“…2 This is, among other things, substantiated by (I) their overrepresentation in reactive lymphatic regions associated with neoplasia, 16 (II) their potential to kill a variety of tumor cells including bladder cancer, 17 colon cancer, 18 glioblastoma multiforme, 19 hematological malignancies 20 and multiple myeloma, 21 and (III) the observed trend between the presence of activated gd T cells in cancer patients and a beneficial outcome. [22][23][24] gd T cells dispose of a sensitive ability to distinguish "foreign" or transformed cells from healthy self-cells, using activating receptors and inhibitory killer Ig-like receptors ( Table 1). gd T cells are therefore not restricted to MHC priming, in contrast to the classic ab T cells, which is a major asset in cancer cell recognition.…”

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

“…Because prostate cancer patients harbor zoledronate-responsive cd cells, 35 a phase I clinical trial in 18 patients with metastatic hormonerefractory prostate cancer was performed by Dieli's group. 36 Subjects were randomized into two groups, which received either zoledronate alone (group A: 4 mg i.v.…”

Osteoimmunology and Cancer - Clinical Implications

“…Zoledronic acid activated T cells in vitro, and administration of ZOL to patients with prostate cancer resulted in the activation of T cells in peripheral blood after the first infusion. Moreover, after the first ZOL infusion, serum prostate-specific antigen (PSA) levels were reduced in 3 of 11 evaluable patients, and PSA velocity was reduced in 5 of 10 evaluable patients [93]. These results suggest that ZOL-activated T cells may be associated with the induction of an anticancer response in patients with prostate cancer.…”