In vivo peripheral expansion of naive CD4+CD25high FoxP3+ regulatory T cells in patients with multiple myeloma.
ABSTRACT In solid tumors, leukemias, and lymphomas, increased frequencies of functional CD4+CD25(high) regulatory T cells (T(reg) cells) have been previously demonstrated. In healthy individuals, T(reg) cells consist not only of memory but also of naive T cells, which can undergo peripheral expansion and are characterized by a relative enrichment for autoreactive T-cell receptors. Here, we demonstrate in patients with premalignant monoclonal gammopathy of undetermined significance and patients with multiple myeloma that functional FoxP3(+) T(reg) cells of naive, central, and effector memory phenotype as determined by CCR7 and CD45RA expression are significantly expanded. Low frequencies of T-cell receptor excision circles in naive T(reg) cells in both healthy controls and multiple myeloma patients point to peripheral expansion as the prominent mechanism of increased frequencies of naive T(reg) cells in these cancer patients. These findings strongly suggest that the increase of functional T(reg) cells in cancer patients is a response to the process of malignant transformation.
Article: Analysis of the immune system of multiple myeloma patients achieving long-term disease control, by multidimensional flow cytometry.[show abstract] [hide abstract]
ABSTRACT: Background. Multiple myeloma remains largely incurable. However, a few patients experience ≥10-years relapse-free survival and can be considered as operationally cured. Interestingly, long-term disease control in multiple myeloma is not restricted to patients with complete response, since some revert into an MGUS profile. Design and Methods. We compared the distribution of multiple compartments of lymphocytes and dendritic cells in the bone marrow and peripheral blood of long-term disease control multiple myeloma (n=28) vs. both newly-diagnosed MGUS (n=23) and symptomatic multiple myeloma (n=23), and age-matched healthy adults (n=10). Results. Similarly to MGUS and symptomatic multiple myeloma, patients with long-term disease control showed an expansion of cytotoxic CD8+T-cells and NK-cells. However, bone marrow Tregs were reduced in long-term disease control vs. symptomatic multiple myeloma. Noteworthy, B-cells were depleted in MGUS and symptomatic multiple myeloma, while recovered in long-term disease control patients in both bone marrow and peripheral blood, due to an increase in normal bone marrow B-cell precursors and plasma cells, as well as pre-germinal center peripheral blood B-cells. The number of bone marrow dendritic cells and tissue macrophages significantly differed between long-term disease control and symptomatic multiple myeloma with a recovery trend in the former patient population towards levels similar to those found in healthy adults.Conclusions. In summary, our results indicate that long-term disease control multiple myeloma patients have a constellation of unique immune changes favoring both immune cytotoxicity and recovery of B-cell production and homing, suggesting an improved immunesurveillance.Keywords: myeloma, long term follow-up, immunesurveillance, T-cells, Tregs, B-cells.Haematologica 07/2012; · 6.42 Impact Factor
Article: Functionally Suppressive CD8 T Regulatory Cells Are Increased in Patients with Multiple Myeloma: A Cause for Immune Impairment[show abstract] [hide abstract]
ABSTRACT: Background: Multiple myeloma (MM) is a plasma cell malignancy frequently associated with impaired immune cell numbers and functions. In MM, several studies have previously shown that CD4 regulatory T (Treg) cells hamper effector T cell functions and enhance immune dysfunction. In this study, we aimed to prove the presence of functionally suppressive Treg cells expressing CD8 phenotype (CD8 Treg cells) in MM. To the best of our knowledge, this has not been reported previously in MM.PLoS ONE 11/2012; · 4.09 Impact Factor
Article: Increased T Regulatory Cells Are Associated with Adverse Clinical Features and Predict Progression in Multiple Myeloma[show abstract] [hide abstract]
ABSTRACT: Background: Regulatory T (Treg) cells play an important role in the maintenance of immune system homeostasis. Multiple myeloma (MM) is a plasma cell disorder frequently associated with impaired immune cell numbers and functions.PLoS ONE 10/2012; · 4.09 Impact Factor