Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival

Curiel, Tyler J.; Coukos, George; Zou, Linhua; Álvarez, Xavier; Cheng, Pui; Mottram, Peter; Evdemon-Hogan, Melina; Conejo-Garcia, José R.; Zhang, Lin; Burow, Matthew E.; Zhu, Yun; Wei, Shuang; Kryczek, Ilona; Daniel, Ben; Gordon, Alan N.; Myers, Leann; Lackner, Andrew A.; Disis, Mary L.; Knutson, Keith L.; Chen, Lieping; Zou, Weiping

doi:10.1038/nm1093

Cited by 4,440 publications

(4,131 citation statements)

References 45 publications

Supporting

148

Mentioning

3,850

Contrasting

Unclassified

Order By: Relevance

“…However, macrophages are not the sole IL-10 source in tumors. Studies in human cancer have shown that Treg cells recruited at tumor sites produce abundant IL-10 [37,38], which may work as the main mediator of Treg-cell functional suppression [37]. Conversely, in a murine tumor model, others have shown that CD25 1 -cell depletion and IL-10 receptor blockade exert distinct, though partially overlapping, effects in suppressing DC activation and anti-tumor CD8 1 response [13].…”

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

View full text Add to dashboard Cite

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 ...

show abstract

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

View full text Add to dashboard Cite

show abstract

“…Even with immune recognition of cancer, which can occur in cancer patients and is evidenced by the frequent observation of T cell infiltration into cancerous tissues [70][71][72][73], it is rare for such tumor infiltrating T cells to induce the spontaneous rejection of established tumors. Accumulating evidence indicates that the tumor environment contains cells and cytokines that actively suppress primed effector T cells [74,75].…”

Section: The Immunosuppressive Environment Inside Tumorsmentioning

confidence: 99%

Targeting tumors with LIGHT to generate metastasis-clearing immunity

Yü¹,

Fu²

2008

Cytokine & Growth Factor Reviews

View full text Add to dashboard Cite

Metastastic diseases cause the majority of morbidity and mortality of cancer patients. Established tumors form both physical and immunological barriers to limit immune detection and destruction. Current immunotherapy of vaccination and adoptive transfer shows limited effect at least in part due to the existing barriers in the tumors and depending on the knowledge of tumor antigens. Tumor necrosis factor superfamily member 14 (TNFSF14) LIGHT interacts with stromal cells, dendritic cells, NK cells, naïve and activated T cells and tumor cells inside the tumor tissues via its two functional receptors, HVEM and lymphotoxin β receptor (LTβR). Targeting tumor tissues with LIGHT leads to augmentation of priming, recruitment, and retention of effector cells at tumor sites, directly or indirectly, to induce strong anti-tumor immunity to inhibit the growth of primary tumors as well as eradicate metastases. Intratumor treatment would break tumor barriers and allow strong immunity against various tumors without defining tumor antigens. This review summarizes recent findings to support that LIGHT is a promising candidate for an effective cancer immunotherapy.

show abstract

“…Tregs play a key role in the prevention of T-cell responses to self-antigens. However, tumors can take advantage of Tregs by attracting them and manipulating Tregmediated immunosuppression in order to escape recognition and elimination by the host [20]. Their role in tumor progression is highlighted by the observation that systemic depletion of Tregs results in reduced tumor growth and increased survival in several models [21].…”

Section: Introductionmentioning

confidence: 99%

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3⁺ Treg

et al. 2009

View full text Add to dashboard Cite

Gliomas localized within the CNS are generally not rejected by the immune system despite being immunogenic. This failure of the immune system has been associated both with glioma-derived immunosuppressive molecules and the immune-privileged state of the CNS. However, the relative contribution of tumor location to the glioma-mediated immunosuppression, as well as the immune mechanisms involved in the failure of glioma rejection are not fully defined. We report here that syngeneic GL261 gliomas growing either intracranially or subcutaneously in mice are infiltrated by DC and T cells. However, only subcutaneous gliomas elicit an effective anti-tumor immune response. In contrast to DC infiltrating subcutaneously grown GL261 gliomas, tumor-infiltrating DC from intracranial gliomas do not activate antigen-dependent T-cell proliferation in vitro. In addition, brain-localized GL261 gliomas are characterized by significantly higher numbers of Foxp3 1 Treg and higher levels of TGF-b1 mRNA and protein expression when compared with GL261 gliomas in the skin. Our data show that gliomas in the CNS, but not in the skin, give rise to TGF-b production and accumulation of both Treg and functionally impaired DC. Thus, not the tumor itself, but its location dictates the efficiency of the antitumor immune response.Key words: DC . Immune privilege . Treg . Tumor immunity Supporting Information available online IntroductionMalignant gliomas, especially the most frequent and aggressive form known as glioblastoma multiforme, are among the most fatal types of tumors. The best standard of care for glioblastoma multiforme, consisting of surgery followed by radiotherapy and chemotherapy with temozolomide, is associated with a median overall survival of 14.6 months following diagnosis [1]. Gliomas have been shown to result in reduced peripheral T-cell responses [2], down-modulated function of circulating APC [3] and particularly to suppressed maturation of peripheral DC [4]. In addition, the localization of the glioma within the immune-privileged CNS, combined with the production of tumorderived immunosuppressive molecules including , , VEGF [9] and prostaglandins [10], is suggested to account for the absence of a successful anti-tumor immune Ã These authors contributed equally to this work. response. As a consequence, glioma patients fail to generate an effective immune response against the intracranially growing tumors. Although it occurs rarely, gliomas are able to metastasize to locations outside of the brain [11]. The low frequency of peripheral glioma metastases might be due to an efficient recognition of tumor cells outside of the CNS. Gliomas express tumor-associated antigens such as ER-2, gp100, and MAGE-1, which can be recognized by cytotoxic T lymphocyte clones [12]. Furthermore, T-cell clonal expansion has been detected in glioma patients [13] and vaccination of patients with autologous tumor lysate-pulsed DC or autologous tumor peptide-pulsed DC [14] can elicit tumor-specific T-cell responses and infiltration of cytotoxic and me...

show abstract

Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival

Cited by 4,440 publications

References 45 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

Targeting tumors with LIGHT to generate metastasis-clearing immunity

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3⁺ Treg

Contact Info

Product

Resources

About

Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival

Cited by 4,440 publications

References 45 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

Targeting tumors with LIGHT to generate metastasis-clearing immunity

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3+ Treg

Contact Info

Product

Resources

About

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3⁺ Treg