γδ T Cells Predict Outcome in Zoledronate-Treated Breast Cancer Patients

Abstract

We read with great interest the article by Valachis et al. [1], published in The Oncologist. In a comprehensive meta-analysis of 15 randomized clinical trials on adjuvant therapy for breast cancer patients with zoledronate, the authors identified a significant overall survival benefit with zoledronate treatment, in agreement with one smaller meta-analysis [2] but not another [3] conducted earlier. These new findings support the call for zoledronate to be considered as a new standard of care in adjuvant breast cancer therapy [4].The dilemma remains that the biological mechanism underlying the antitumor role of zoledronate is unclear, as Valachis et al. correctly highlight [1]. The clinical benefit may in fact stem, at least in part, from the activity of zoledronate on the patient's immune system by specifically stimulating V␥9/V␦2 T cells, which compose 0.5%-5% of circulating T cells in healthy adults [5]. Targeted immunotherapy studies directly exploiting the potent non-major histocompatibility complexrestricted cytotoxicity of V␥9/V␦2 T cells have shown excellent safety profiles and promising clinical observations in a variety of hematological and solid cancers [6], including metastatic breast cancer [7].Studies by us and others have demonstrated that zoledronate treatment induces a rapid and long-lasting conversion of the peripheral V␥9/V␦2 T-cell phenotype from CD27 ϩ CD45RA Ϫ central memory T (T CM ) cells to CD27 Ϫ CD45RA Ϫ effector memory T (T EM ) cells in many, but not all, individuals [7][8][9]. In Figure 1, zoledronate-treated breast cancer patients with stable disease showed elevated proportions of V␥9/V␦2 T EM cells at the time of blood sampling compared with patients with progressing disease and untreated controls (Fig. 1A). No such differences were observed with regard to patient age, time on treatment, or pretreatment clinical status. We then stratified the same patient cohort according to their follow-up disease status at 3-9 months after blood sampling. This showed successful conversion from T CM to T EM cells (as evident by a lower frequency of T CM cells) in patients who were stable 3-9 months after blood sampling compared with patients who went on to show progressing disease (Fig. 1B).Our analysis illustrates the diagnostic and prognostic potential of a ␥␦ T-cell-based blood test and implies a link between immune responsiveness and positive outcome with zoledronate therapy, thereby contributing to our understanding of the as yet unexplained clinical benefit of adjuvant therapy. These findings are particularly intriguing because new treatments specifically targeting bone resorption, such as denosumab, lack this potential to act on CD45RAϪ centralmemoryTcellsinrelationtosubsequent clinical outcome at 3-9 months after sampling. Patients received at least two cycles of zoledronic acid (Zometa; Novartis International, Basel, Switzerland, http://www.novartis.com) for Ͼ1 monthandϽ8monthsandhadnootheractivemalignancieswithinthe previousyear;noactiveoruncontrolledinfections;noautoimmunedisorders or ...

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“…This skewed phenotype of peripheral Vγ9Vδ2 T cells was strikingly depicted by the raw data for patient #7 shown in Fig 2B . Overall, the statistically significant changes in circulating Vγ9Vδ2T cell subset distribution indicate that a long-term effector maturation and mobilization of peripheral blood Vγ9Vδ2 T cells occur in subjects after melanoma removal and evoke previous observations after Zoledronate injection in cancer patients [ 33 , 34 ].…”

Pathogen-Specific Immune Fingerprints during Acute Infection: The Diagnostic Potential of Human γδ T-Cells

“…Thirty years after the unexpected cloning of the TCRγ chain (59, 60) and 20 years after the first description of microbial “phosphoantigens” as specific activators of human Vγ9/Vδ2 T-cells (61, 62), the diagnostic potential of γδ T-cells is only beginning to unfold (34, 47, 63, 64). …”

In Reply

“…Although we agree with Dr. Kapoor regarding the plausible scientific rationale for such an underlying mechanism, we were unable to examine such a hypothesis because of the lack of subgroup analysis based on the use of radiotherapy in the trials included in our meta-analysis. In this regard, future randomized trials and individual patient data meta-analysis may need to focus on this area.A new insight on the biological mechanism behind the antitumoral activity of ZA is presented in the letter by Dr. Welton and colleagues [10]. The higher proportion of V␥9/V␦2 effector memory T cells in breast cancer patients treated with ZA compared with untreated patients or patients with progress, as demonstrated in the authors' original data, supports the hypothesis that ZA could serve as an immunomodulating factor and may trigger antitumoral activity through higher immune responsiveness against breast cancer cells.…”

“…A new insight on the biological mechanism behind the antitumoral activity of ZA is presented in the letter by Dr. Welton and colleagues [10]. The higher proportion of V␥9/V␦2 effector memory T cells in breast cancer patients treated with ZA compared with untreated patients or patients with progress, as demonstrated in the authors' original data, supports the hypothesis that ZA could serve as an immunomodulating factor and may trigger antitumoral activity through higher immune responsiveness against breast cancer cells.…”