Local and systemic induction of CD4+CD25+ regulatory T-cell population by non-Hodgkin lymphoma

Abstract

IntroductionB-cell non-Hodgkin lymphoma (NHL) is a heterogeneous group of lymphoid malignancies, many of which remain incurable. Increasing evidence suggests that the tumor microenvironment plays an important role, in determining not only the severity of disease, but also response to therapy. [1][2][3][4] Ansell et al 4 demonstrated that higher numbers of activated CD4 ϩ cells among the tumor-infiltrating lymphocytes of diffuse large B-cell NHL were associated with a better prognosis. More recently, analyses of gene expression using microchips in follicular and diffuse large B-cell lymphomas have indicated that the nature of nonmalignant lymphocytes is important prognostically. 5,6 It is becoming clear that a critical component of the immune response to malignancies includes regulatory T (Treg) cells. 7 There are at least 2 forms of Treg cells, "natural" and "induced." The former suppress, at least in vitro, via undefined mechanisms dependent on cell-cell contact; the latter inhibit primarily through the secretion of immunosuppressive cytokines such as IL-10. 8 Natural Treg cells constitutively express high levels of CD25 and are believed to arise as a suppressive population in Hassall corpuscles within the thymus, 9 but there is evidence that they may also arise peripherally. 10 There have been difficulties in identifying unique markers for the natural population. 7 Expression of the forkhead/winged helix transcription factor (FoxP3) The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 10, 2018. by guest www.bloodjournal.org FromWe therefore enumerated Treg cells in peripheral blood and involved tissue samples from NHL patients and determined whether the tumor cells induce their differentiation. Methods PatientsBetween January 2006 and February 2007, 30 newly diagnosed patients with B-cell NHL (age range: 17 to 93 years, mean ϭ 62, SD ϭ 22) were recruited from Aberdeen Royal Infirmary, United Kingdom, which is the sole specialty hospital serving the Grampian area. The study received approval from The Grampian NHS local ethics committee, Aberdeen, and informed consent was obtained from all patients in accordance with the Declaration of Helsinki. An age-matched control group comprised 13 healthy individuals (age range: 20 to 90 years, mean ϭ 58, SD ϭ 17) admitted for minor surgical procedures and 2 individuals with benign lymphadenopathy. Patient characteristics are described in Table 1. All initial samples were obtained before any antilymphoma treatment was given. ReagentsThe control recall antigens, mycobacterial PPD (Statens Seruminstitut, Copenhagen, Denmark), diphtheria, poliomyelitis, and tetanus (DPT) vaccine (Aventis Pasteur, Strasbourg, France), T-cell mitogen concanavalin A (ConA; SigmaAldrich, Amersham, United Kingdom), and anti-CD3/28 Dynabeads (Dyn...

Vaccination with autologous tumor-loaded dendritic cells induces clinical and immunologic responses in indolent B-cell lymphoma patients with relapsed and measurable disease: a pilot study

“…33 To verify whether our DC-based vaccination could counteract this mechanism and restore the physiologic balance of Tregs in the PB and at the tumor site, the frequency of CD4 ϩ CD25 ϩ FOXP3 ϩ T cells was evaluated for the enrolled patients before and after vaccination. At the time of the enrollment, NHL patients had a higher frequency of Tregs in the PB (P ϭ .096) and LNs (P Ͻ .001) in comparison with healthy donors ( Figure 2A).…”

Elevated frequencies of CD4+CD25+CD127lo regulatory T cells is associated to poor prognosis in patients with acute myeloid leukemia

“…Treg have been shown to be overrepresented in patients with various cancers, including lung, breast, pancreatic, ovarian and melanoma and able to suppress antitumor immune responses. [8][9][10][11][12] Circulating Treg also increased in hematological malignancies including non-Hodgkin's lymphoma, 13 chronic lymphocytic leukemia, 14,15 acute myeloid leukemia (AML), 16 multiple myeloma 17 and myelodysplasia syndrome. 18 Several reports have been shown that increased frequencies of circulating CD4 þ…”

Tumor-Infiltrating Monocytic Myeloid-Derived Suppressor Cells Mediate CCR5-Dependent Recruitment of Regulatory T Cells Favoring Tumor Growth

“…Accordingly, the depletion of Tregs results in improved antitumor immune responses and delays tumor growth in many tumor models (15). High numbers of Tregs in tumors such as lymphoma (16) are often associated with poor prognosis for cancer patients. Several mechanisms of Treg recruitment to tumors were reported.…”