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Viruses exploit a number of strategies to evade immune recognition. In this study, we describe a novel mechanism by which EBV, rather than avoiding detection, subverts the immune response by stimulating regulatory T cells that secrete IL-10. Human PBMC from all EBV-seropositive, but not -seronegative, donors responded to both purified latent membrane protein 1 and the corresponding immunodominant peptides with high levels of IL-10 secretion by CD4+ T cells. These IL-10 responses, characteristic of T regulatory 1 cells, inhibited T cell proliferation and IFN-γ secretion induced by both mitogen and recall Ag. It was confirmed that the inhibition was IL-10 dependent by the use of neutralizing Ab. The deviation of the immune response toward suppression is likely to be important in maintaining latency and EBV-associated tumors.

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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...

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The immunosuppressive microenvironment in tumors hampers the induction of antitumor immunity by vaccines or immunotherapies. Toll-like receptor (TLR) ligands have the potential to treat tumors, but they can exert a mixture of positive and negative effects on inflammation in the tumor microenvironment. In this study, we show that specific small molecule inhibitors of phosphoinositide 3-kinase (PI3K) relieve immunosuppression to heighten the proinflammatory effects of TLR ligands that support antitumor immunity. Multiple strategies to inhibit PI3K in dendritic cells (DC) each led to suppression of interleukin (IL)-10 and TGF-b but did affect IL-12 or IL-1b induction by the TLR5 ligand flagellin. In three different mouse models of cancer, combining flagellin with a class I PI3K inhibitor, either with or without a DC vaccine, delayed tumor growth and increased survival, with some animals exhibiting complete rejection and resistance to secondary challenge. Tumor growth suppression was associated with increased accumulation of polyfunctional T cells that secreted multiple effector cytokines, including IFN-g, IL-17, and IL-2. Therapeutic protection was abolished in mice deficient in IL-17 or deprived of IFN-g. Together, our results indicate that PI3K inhibition heighten the antitumor properties of TLR ligands, eliciting tumor regression directly but also indirectly by relieving suppressive signals that restrict potent antitumor T-cell responses. These findings suggest important uses for PI3K inhibitors in heightening responses to cancer immunotherapy and immunochemotherapy. Cancer Res; 72(3); 581-91. Ó2011 AACR.

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