Myeloid-derived suppressor cells (MDSC) expand in tumor-bearing hosts and play a central role in cancer immune evasion by inhibiting adaptive and innate immunity. They therefore represent a major obstacle for successful cancer immunotherapy. Different strategies have thus been explored to deplete and/or inactivate MDSC in vivo. Using a murine mammary cancer model, we demonstrated that doxorubicin selectively eliminates MDSC in the spleen, blood and tumor beds. Furthermore, residual MDSC from doxorubicin-treated mice exhibited impaired suppressive function. Importantly, the frequency of CD4+ and CD8+ T lymphocytes and consequently the effector lymphocytes or natural killer (NK) to suppressive MDSC ratios were significantly increased following doxorubicin treatment of tumor-bearing mice. In addition, the proportion of natural killer (NK) and cytotoxic T cell (CTL) expressing perforin and granzyme B and of CTL producing IFNγ was augmented by doxorubicin administration. Of therapeutic relevance, this drug efficiently combined with Th1 or Th17 lymphocytes to suppress tumor development and metastatic disease. MDSC isolated from patients with different types of cancer were also sensitive to doxorubicin-mediated cytotoxicity in vitro. These results thus indicate that doxorubicin may be used not only as a direct cytotoxic drug against tumor cells, but also as a potent immunomodulatory agent that selectively impairs MDSC-induced immunosuppression, thereby fostering the efficacy of T cell-based immunotherapy.

Objective. From an immunologic standpoint, the mechanisms by which treatment with tocilizumab (TCZ), a humanized anti-interleukin-6 (anti-IL-6) receptor antibody, results in improvement in rheumatoid arthritis (RA) patients are still not fully understood. In vitro studies and studies in mouse models have demonstrated the critical role of IL-6 in Th17 cell differentiation. Th17 lymphocytes have been shown to be strongly involved in RA pathogenesis, and the purpose of this study was to investigate the effect of IL-6 blockade on the balance between Th17 cells and Treg cells in patients with active RA.Methods. Patients with active RA for whom TCZ had been prescribed by a rheumatologist were enrolled in this study. Phenotypic analyses of T cell populations were performed, and the Disease Activity Score in 28 joints (DAS28) was assessed. Serum cytokine levels and other parameters of inflammation were measured before the first infusion and after the third infusion of TCZ (8 mg/kg). Results. Compared to controls, levels of Th17 cells (CD4؉IL-17؉

Objective. Giant cell arteritis (GCA) is the most frequently occurring vasculitis in elderly individuals, and its pathogenesis is not fully understood. The objective of this study was to decipher the role of the major CD4؉ T cell subsets in GCA and its rheumatologic form, polymyalgia rheumatica (PMR).Methods. A prospective study of the phenotype and the function of major CD4؉ T cell subsets (Th1, Th17, and Treg cells) was performed in 34 untreated patients with GCA or PMR, in comparison with 31 healthy control subjects and with the 27 treated patients who remained after the 7 others withdrew. Results. Compared with control subjects, patients with GCA and patients with PMR had a decreased frequency of Treg cells and Th1 cells, whereas the percentage of Th17 cells was significantly increased.Furthermore, an analysis of temporal artery biopsy specimens obtained from patients affected by GCA for whom biopsy results were positive demonstrated massive infiltration by Th17 and Th1 lymphocytes without any Treg cells. After glucocorticoid treatment, the percentages of circulating Th1 and Th17 cells decreased, whereas no change in the Treg cell frequency was observed. The frequency of CD161؉CD4؉ T cells, which are considered to be Th17 cell precursors, was similar in patients and control subjects. However, these cells highly infiltrated GCA temporal artery biopsy specimens, and their ability to produce interleukin-17 in vitro was significantly enhanced in patients with GCA and patients with PMR and was correlated with a decrease in the phosphorylated form of STAT-1.Conclusion. This study is the first to demonstrate that the frequency of Treg cells is decreased in patients with GCA and patients with PMR, and that CD161؉CD4؉ T lymphocytes, differentiated into Th1 cells and Th17 cells, are involved in the pathogenesis of GCA and PMR.Giant cell arteritis (GCA) is a systemic vasculitis affecting large and medium-sized blood vessels. GCA is characterized by granulomatous infiltration into the layers of the aorta and its major branches in association with systemic inflammation, leading to anemia, polymyalgias, and weakness. Classic clinical features of GCA include temporal headache, scalp tenderness, or tender

I matinib mesylate (Gleevec) therapy remains the standard of care for patients with chronic myelogenous leukemia (CML).3 Designed as a selective competitive inhibitor of the Abelson (ABL) tyrosine kinases (BCR-ABL, v-ABL, c-ABL), this drug leads to growth arrest or apoptosis (1, 2). Imatinib also displays strong activity against the platelet-derived growth factor receptor, c-kit receptor, ABL-related gene, and their fusion proteins (1-3) and thus has also been used for the therapy of gastrointestinal stromal tumors with mutations in c-kit (2).However, the specificity of this molecule may be broader than originally expected, and it is becoming increasingly evident that imatinib also inhibits key tyrosine kinases in immune cells. The exact nature of imatinib effects (activation or suppression) on lymphocytes or dendritic cells remains controversial. Inhibition of CD4 ϩ or CD8 ϩ T cell proliferation and activation by imatinib has been documented (4 -8). Some reports have further highlighted the negative effect of imatinib on the TCR-induced ZAP70 signaling pathway identifying the leukocyte-specific protein tyrosine kinase (Lck) as a potential molecular target (4, 9). Similarly, a negative modulation of dendritic cell (DC) development by imatinib and a down-regulation of their Ag-presenting function have also been described (10 -12). In contrast to these findings, it has been reported that imatinib does not impede the immunogenicity of DC (13) and may enhance their Ag-presenting function (14). Additionally, some reports indicate that imatinib may foster DC-NK reciprocal activation, thereby promoting the antitumoral function of NK cells (15). CD4 ϩ CD25 ϩ regulatory T lymphocytes (Treg) critically contribute to the maintenance of self-tolerance and to the prevention of autoimmunity in animals and humans (16, 17). These suppressive cells have also been highlighted as major contributors in the establishment and persistence of cancer-induced immune tolerance (18,19). Treg expansion detected in the blood, lymph nodes, and spleens of tumor-bearing hosts (20 -23) may result from the conversion of CD4 ϩ CD25 Ϫ T cells into CD4 ϩ CD25 ϩ Treg (24) or from the proliferation of naturally occurring Treg (25). Tumorinduced Treg compromise the function of anti-tumor effector CD8 ϩ T cells, curtail CD4 ϩ T cell help, impede Ag-presenting cell activity (18,23,26) and therefore represent a major obstacle for successful cancer immunotherapy. In support of this concept, studies in humans and in animal models have demonstrated that attempts to disrupt Treg suppressive activity promote antitumoral immunity (20,27,28). Different strategies have thus been evaluated to deplete or inactivate Treg and include the use of anti-CD25 Abs, the IL-2/diphtheria toxin fusion protein, the immunotoxin The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.1 This work was supported in p...

Immune thrombocytopenia (ITP) is an autoimmune disease with a complex pathogenesis. As in many B cell-related autoimmune diseases, rituximab (RTX) has been shown to increase platelet counts in some ITP patients. From an immunologic standpoint, the mode of action of RTX and the reasons underlying its limited efficacy have yet to be elucidated. Because splenectomy is a cornerstone treatment of ITP, the immune effect of RTX on this major secondary lymphoid organ was in-