Reconstitution of regulatory T cells after autologous transplantation in multiple myeloma

Abstract

Regulatory T cells are immunosuppressive subsets of CD4? T cells [1]. Their numbers are increased in some cancers and they have been implicated in the suppression of anti-tumor immunity and thus the promotion of tumor growth and survival [1]. It has been reported that regulatory T cells are reduced in treatment-naive patients with multiple myeloma (MM) [2]. This difference has been attributed to the unique cytokine milieu in MM, which is rich both in IL-6 and TGF-b, cytokines favoring the development of TH17 cells over regulatory T cells [3]. There is limited data on the kinetics of regulatory T cells’ reconstitution after autologous stem cell transplant (ASCT), one of the standard treatments for MM. We assessed recovery of regulatory T cells in six patients who underwent highdose chemotherapy using melphalan (200 mg/m) followed by G-CSF mobilized peripheral blood stem cells transplantation. All the patients had attained either partial response (PR) or very good PR (VGPR) after treatment with thalidomide–dexamethasone (five patients) or vincristine–adriamycin–dexamethasone (one patient) based therapy in the pre-transplant phase. Blood samples were collected in the pre-transplant period, and 6 months after ASCT. Regulatory T cells were identified as cells with a CD4? CD25 to high CD127 FoxP3? phenotype, using techniques described previously [2]. We observed a preferential increase in the number of regulatory T cells in the post-transplant period. These values were higher than the pre-transplant values (P = 0.03) and approached levels seen in healthy control population (Table 1). The CD4 cells as a whole had not recovered at 6 months and the CD4:CD8 ratio remained low compared to control subjects (P = 0.001) as well as pre-transplant values (P = 0.03). Of the six patients, three achieved complete response (CR) and three achieved VGPR at 6 months post-transplant. Recovery of immune subsets in the post-stem cell transplant period has been detailed, and the phenomenon of early recovery of CD8? T cells and NK cells and the delayed recovery of CD4? T cells is well known [4]. Recently, a number of investigators have addressed the issue of the reconstitution of regulatory T cells, and have demonstrated their preferential and early recovery [5, 6]. At present, it is not known whether the pattern of recovery of T-cell subsets after transplant depends on the process of transplant per se, or on the effect of residual disease. Following ASCT, various degrees of residual disease may persist, which may affect immune reconstitution [7]. Posttransplant recovery of immune function has also been correlated with disease outcome in many cancers, including MM [8]. In the post-allogenic transplant setting, regulatory T cells have been shown to preferentially inhibit graft versus host disease, while allowing the graft versus tumor effect to persist [9]. Atanackovic et al. [5] demonstrated that donorderived regulatory T cells reconstitute early as compared to the CD4? T-cell population as a whole after allogenic stem cell transplantation in MM patients. In this study, we report an early and preferential recovery of regulatory T cells as compared to CD4? cells, demonstrating that the regulatory P. Ganeshan L. Kumar A. Sharma Department of Medical Oncology, Dr. B.R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences (AIIMS), Ansari Nagar, New Delhi 110029, India