Importance of IL-10 for CTLA-4-Mediated Inhibition of Tumor-Eradicating Immunity

Jovasevic, Vladimir M.; Gorelik, Leonid; Bluestone, Jeffrey A.; Mokyr, Margalit B.

doi:10.4049/jimmunol.172.3.1449

Cited by 39 publications

(26 citation statements)

References 31 publications

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“…Considering that CD80 can bind to CTLA-4 with a higher avidity and that anti-CTLA-4 FAb blocked the TGF-␤1-inducing effect of dominant costimulation by CD80 clearly indicated that CD80-CTLA-4 interaction is important for the induction of suppressor cytokines and the regulatory phenotype of T cells. Previous studies demonstrating that signaling through CTLA-4 using agonistic Abs can induce IL-10 response (15,16,38) also corroborate this notion. Addition of anti-CD28 FAb along with anti-CD86 or anti-CD80 Ab not only resulted in the suppression of T cell proliferation, but also inhibited both inflammatory and suppressor cytokine responses (not shown) suggesting that initial activation of T cells through CD28 is critical in the Treg-inducing effect of dominant costimulation by CD80.…”

Section: Discussionsupporting

confidence: 73%

Preferential Costimulation by CD80 Results in IL-10-Dependent TGF-β1+-Adaptive Regulatory T Cell Generation

Pérez¹,

Karumuthil‐Melethil²,

Li³

et al. 2008

The Journal of Immunology

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Costimulatory ligands CD80 and CD86 have different binding preferences and affinities to their receptors, CD28 and CTLA-4. Earlier, we demonstrated that CD80 binds to CTLA-4 with higher affinity and has a role in suppressing T cell response. The current study demonstrates that not only did blockade of CD86 upon Ag presentation by bone marrow-derived dendritic cells (DC) to OVA-specific T cells result in induction of hyporesponsive T cells but also that these T cells could suppress the proliferative response of effector T cells. These T cells showed TGF-β1 on their surface and secreted TGF-β1 and IL-10 upon restimulation. Although blockade of CTLA-4 and neutralization of IL-10 profoundly inhibited the induction of these TGF-β1+ T cells, their ability to suppress the effector T cell proliferation was abrogated by neutralization of TGF-β1 alone. Induction of TGF-β1+ and IL-10+ T cells was found to be independent of natural CD4+CD25+ regulatory T cells, demonstrating that preferential ligation of CTLA-4 by CD80 induced IL-10 production by effector T cells, which in turn promoted the secretion of TGF-β1. Treatment of prediabetic NOD mice with islet β cell Ag-pulsed CD86−/− DCs, but not CD80−/− DCs, resulted in the induction of TGF-β1- and IL-10-producing cells, significant suppression of insulitis, and delay of the onset of hyperglycemia. These observations demonstrate not only that CD80 preferentially binds to CTLA-4 but also that interaction during Ag presentation can result in IL-10-dependent TGF-β1+ regulatory T cell induction, reinstating the potential of approaches to preferentially engage CTLA-4 through CD80 during self-Ag presentation in suppressing autoimmunity.

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Section: Discussionsupporting

confidence: 73%

Preferential Costimulation by CD80 Results in IL-10-Dependent TGF-β1+-Adaptive Regulatory T Cell Generation

Pérez¹,

Karumuthil‐Melethil²,

Li³

et al. 2008

The Journal of Immunology

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“…5). This may be due to IL-10 secretion of Colo201 tumor cells (data not shown), which was demonstrated to suppress IFN-␥ secretion of activated T cells (22).…”

Section: Resultsmentioning

confidence: 99%

T Cell Activation by Antibody-Like Immunoreceptors: Increase in Affinity of the Single-Chain Fragment Domain above Threshold Does Not Increase T Cell Activation against Antigen-Positive Target Cells but Decreases Selectivity

Chmielewski

Hombach

Heuser

et al. 2004

The Journal of Immunology

242

223

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Chimeric TCRs with an Ab-derived binding domain confer predefined specificity and MHC-independent target binding to T cells for use in adoptive immunotherapy. We investigated the impact of receptor binding affinity on the activation of grafted T cells. A series of anti-ErbB2 single-chain fragment binding domains with a Kd ranging from 3.2 × 10−7 to 1.5 × 10−11 M was linked to CD3ζ-derived immunoreceptors and expressed in human PBL. Solid phase bound ErbB2 protein triggered activation of receptor-grafted T cells in a dose-dependent manner. The activation threshold inversely correlated with the affinity of the receptor binding domain. The maximum level of cellular activation, however, was the same and independent of the binding affinity. Upon binding to ErbB2+ cells, T cells grafted with immunoreceptors carrying a single-chain fragment of Kd < 10−8 M were activated in a similar fashion against cells with different amounts of ErbB2 on the surface. T cells with a low affinity receptor (Kd > 10−8 M), however, were activated exclusively by cells with high amounts of ErbB2. In conclusion, recombinant immunoreceptors of higher affinity do not necessarily induce a more potent activation of T cells than low affinity immunoreceptors, but the higher affinity immunoreceptors exhibit less discrimination between target cells with high or low Ag expression levels.

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“…IL-10, a Thelper 2 type cytokine, also known to be produced by melanoma cells, can counteract the activities of IFN-g and other T-helper 1 immune-stimulatory cytokines, and blunt antitumor T-cell responses (41 -43). IL-10 has also recently been implicated in the inhibition of the generation of antitumor T cells mediated via CTL antigen 4 (44). In contrast, some investigators have observed that IL-10 can mediate melanoma regression in animal models and advocate administration of IL-10 as an antitumor agent in humans (45,46).…”

Section: Discussionmentioning

confidence: 99%

Phase I Study of the Intratumoral Administration of Recombinant Canarypox Viruses Expressing B7.1 and Interleukin 12 in Patients with Metastatic Melanoma

Triozzi

Allen

Carlisle

et al. 2005

Clinical Cancer Research

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The objective of this study was to evaluate the safety and activity of the intratumoral administration of the immune costimulatory molecule, B7.1, encoded by a vector derived from the canarypox virus, ALVAC (ALVAC-B7.1), alone and with the intratumoral injection of ALVAC encoding the immune-stimulatory cytokine, interleukin 12 (ALVAC-IL-12). Fourteen patients with metastatic melanoma who had s.c. nodules received intratumoral injections on days 1, 4, 8, and 11. Nine patients were given escalating doses of up to 25 Â 10 8 plaque-forming units of ALVAC-B7.1. Five patients were given 25 Â 10 8 plaque-forming units of ALVAC-B7.1combined with ALVAC-IL-12 50% tissue culture infective dose of 2 Â 10 6 .Toxicity was mild to moderate and consisted ofinflammatory reactions at the injection site and fever, chills, myalgia, and fatigue. Higher levels of B7.1 mRNA were observed in ALVAC-B7.1^injected tumors compared with saline-injected control tumors. Higher levels of intratumoral vascular endothelial growth factor and IL-10, cytokines with immune suppressive activities, were also observed in ALVAC-B7.1^and ALVAC-IL-12^injected tumors compared with saline-injected controls. Serum levels of vascular endothelial growth factor increased at day 18 and returned to baseline at day 43. All patients developed antibody to ALVAC. Intratumoral IL-12 and IFN-g mRNA decreased. Changes in serum IL-12 and IFN-g levels were not observed. Tumor regressions were not observed. The intratumoral injections of ALVAC-B7.1and ALVAC-IL-12 were well tolerated at these dose levels and at this schedule and resulted in measurable biological response. This response included the production of factors that may suppress the antitumor immunologic activity of these vectors.

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Importance of IL-10 for CTLA-4-Mediated Inhibition of Tumor-Eradicating Immunity

Cited by 39 publications

References 31 publications

Preferential Costimulation by CD80 Results in IL-10-Dependent TGF-β1+-Adaptive Regulatory T Cell Generation

Preferential Costimulation by CD80 Results in IL-10-Dependent TGF-β1+-Adaptive Regulatory T Cell Generation

T Cell Activation by Antibody-Like Immunoreceptors: Increase in Affinity of the Single-Chain Fragment Domain above Threshold Does Not Increase T Cell Activation against Antigen-Positive Target Cells but Decreases Selectivity

Phase I Study of the Intratumoral Administration of Recombinant Canarypox Viruses Expressing B7.1 and Interleukin 12 in Patients with Metastatic Melanoma

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