Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40

Sotomayor, Eduardo M.; Borrello, Ivan; Tubb, Erev E.; Rattis, Frédérique Marie; Bien, Harold; Lu, Zhengbin; Fein, Steve; Schoenberger, Stephen P.

doi:10.1038/10503

Cited by 382 publications

(276 citation statements)

References 46 publications

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“…DCrestricted CD40 proficiency is necessary and sufficient to induce protective Th1 immunity, through IL-12 production, in a tumor vaccination setting [18]. Three seminal papers demonstrated that CD40 triggering in vivo by an agonist mAb can overcome CD4 1 and CD8 1 T-cell tolerance to tumor-associated antigens and induce tumor eradication [62][63][64]. We have shown that CD40 engagement by CD40L expressed by a tumor-cell vaccine can increase immunity against tumor antigens cross-presented by DCs [27] and that the CD40/CD40L axis is required for CTL induction by vaccination with GM-CSF/OX40L-transduced tumor cells [65].…”

Section: Discussionmentioning

confidence: 99%

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

et al. 2011

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Treg cells maintain the tumor microenvironment in an immunosuppressive state preventing an effective anti-tumor immune response. A possible strategy to overcome Treg-cell suppression focuses on OX40, a costimulatory molecule expressed constitutively by Treg cells while being induced in activated effector T cells. OX40 stimulation, by the agonist mAb OX86, inhibits Treg-cell suppression and boosts effector T-cell activation. Here we uncover the mechanisms underlying the therapeutic activity of OX86 treatment dissecting its distinct effects on Treg and on effector memory T (Tem) cells, the most abundant CD4 1 populations strongly expressing OX40 at the tumor site. In response to OX86, tumor-infiltrating Treg cells produced significantly less interleukin 10 (IL-10), possibly in relation to a decrease in the transcription factor interferon regulatory factor 1 (IRF1). Tem cells responded to OX86 by upregulating surface CD40L expression, providing a licensing signal to DCs. The CD40L/CD40 axis was required for Tem-cellmediated in vitro DC maturation and in vivo DC migration. Accordingly, OX86 treatment was no longer therapeutic in CD40 KO mice. In conclusion, following OX40 stimulation, blockade of Treg-cell suppression and enhancement of the Tem-cell adjuvant effect both concurred to free DCs from immunosuppression and activate the immune response against the tumor. 3615The tumor microenvironment is characterized by an immunosuppressive cytokine milieu, which promotes immune tolerance and tumor growth. Treg cells secrete interleukin 10 (IL-10), which plays a critical role in suppressing immune responses and in particular the maturation of fully competent DCs [13][14][15]. Among tumor-infiltrating Teff cells, the subpopulation of effector memory T (Tem) cells is the most abundant. Tem cells are CD4 1 CD44 high CD62L low lymphocytes excluded from resting lymph nodes and mainly localized in peripheral tissues; upon stimulation they rapidly activate and secrete effector cytokines like IFN-g, but they have limited proliferative capacity [16]. In experimental models of immune activation, Tem cells constitutively express CD40L at levels sufficient to induce DC activation in an antigen-independent manner [17]. The CD40/CD40L axis is crucial for DC maturation and the subsequent T-cell priming. However in the tumor microenvironment this costimulatory pathway is often dampened, thus impairing the generation of an efficient anti-tumor immune response [18,19].In this study we have investigated the mechanisms by which OX86 modulates Treg-and Teff-cell functions and their reciprocal interactions with DCs at the tumor site. We propose a model of the tumor microenvironment in which, after OX86 treatment, DCs receive a lower IL-10-mediated inhibition by Treg cells on the one hand, and a stronger stimulation from Tem cells, via the CD40/CD40L axis, on the other. In this favorable condition, DCs acquire a stronger migratory ability toward the draining LNs (dLNs), thus inducing a specific anti-tumor immune response. ResultsIntratumoral ...

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Section: Discussionmentioning

confidence: 99%

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

et al. 2011

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“…the antibody could provoke a productive immune response without subsequent immunization [8][9][10][11]. However, these previous studies have used an immunization protocol that gave a sustained Ag stimulus (peptide in IFA for example) [10,28].…”

Section: Cd40-cd154 Signalling Is Not Required For the Induction Of Tmentioning

confidence: 99%

“…These observations led to studies that have employed exogenous stimulation of this CD40-OX40 pathway with agonistic antibodies to prevent the induction of T cell tolerance. This can be done either at the surface of the APC (using anti-CD40) [8][9][10][11] or the surface of the T cell (using anti-OX40) [12,13]. Clearly the use of either approach to stimulate an immune response that is otherwise inadequate, or even one that might otherwise lead to tolerance (such as the poor immunogenicity of tumour Ag), can have potential therapeutic benefits.…”

Section: Introductionmentioning

confidence: 99%

Circumventing tolerance at the T cell or the antigen‐presenting cell surface: Antibodies that ligate CD40 and OX40 have different effects

2006

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An adjuvant can be defined as an agent that non‐specifically promotes the immune response to an accompanying antigen. Ligation of CD40 on the surface of the antigen‐presenting cell leads to upregulation of OX40 ligand which, in turn, ligates OX40 on the activated T cell resulting in prolonged T cell proliferation/survival, boosting the immune response. Thus agonistic anti‐CD40 and anti‐OX40 might be viewed as “adjuvant antibodies” and have been shown in diverse experimental systems to either boost immune responses or prevent the establishment of immunological tolerance. Here we describe that both these antibodies are able to prevent the induction of tolerance induced using soluble peptide antigen. However, unlike lipopolysaccharide, they are not sufficient to convert tolerance to immunity (i.e. they are not true adjuvants in this system). Using mice that are prone to either Th1 or Th2 immunity under identical immunization conditions, we show that the effects of anti‐OX40 are quantitative – boosting whichever response is dominant. In contrast, anti‐CD40 boosts Th1 immunity and converts a Th2 response to Th1. We conclude that, although these two antibodies seem to impact on the same molecular pathway of costimulation to prevent tolerance, their effects are qualitatively distinct and their use cannot be viewed as interchangeable.

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“…5 Recent studies have revealed that the state of activation and /or maturation of antigen-presenting cells ( APCs ) may determine whether T cells are primed or rendered tolerant. 6 CD40 is a member of the tumor necrosis factor ( TNF ) receptor family of cell surface proteins expressed on B cells, macrophages, and dendritic cells. It binds a CD40 ligand (CD40L /CD154 ), which is a member of the TNF superfamily expressed on activated T cells, basophils, and mast cells.…”

mentioning

confidence: 99%

Induction of antitumor immunity by transduction of CD40 ligand gene and interferon-γ gene into lung cancer

et al. 2001

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Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40

Cited by 382 publications

References 46 publications

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

Circumventing tolerance at the T cell or the antigen‐presenting cell surface: Antibodies that ligate CD40 and OX40 have different effects

Induction of antitumor immunity by transduction of CD40 ligand gene and interferon-γ gene into lung cancer

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