Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti–CTLA-4 antibodies

Peggs, Karl S.; Quezada, Sergio A.; Chambers, Cynthia A.; Korman, Alan J.; Allison, James P.

doi:10.1084/jem.20082492

Cited by 832 publications

(613 citation statements)

References 36 publications

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“…However, not all its regulatory effects are explained by inhibitory costimulation, since CTLA-4 can also suppress activated effector T-cell populations without the need for them to express it [9,10]. This latter, cell-extrinsic mechanism has been largely attributed to CD4 + regulatory T (Treg)-cell subsets, which constitutively express high levels of CTLA-4, and require it for their regulatory function [11][12][13][14][15][16].…”

Section: Abstract: Cd4 + T Cells R Costimulatory Molecules R Immune Rmentioning

confidence: 99%

The soluble isoform of CTLA‐4 as a regulator of T‐cell responses

et al. 2013

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CTLA-4 is a crucial immune regulator that mediates both negative costimulation signals to T cells, and regulatory T (Treg)-cell extrinsic control of effector responses.Here we present evidence supporting a novel mechanism for this extrinsic suppression, executed by the alternatively spliced soluble CTLA-4 isoform (sCTLA-4). Analyses of human T cells in vitro show that sCTLA-4 secretion can be increased during responses, and has potent inhibitory properties, since isoform-specific blockade of its activity significantly increased Ag-driven proliferation and cytokine (IFN-γ, IL-17) secretion. Treg cells were demonstrated to be a prominent source of sCTLA-4, which contributed to suppression in vitro when their numbers were limiting. The soluble isoform was also produced by, and inhibited, murine T cells responding to Ag in vitro, and blockade of its activity in vivo protected against metastatic spread of melanoma in mice. We conclude that sCTLA-4 is an important immune regulator, responsible for at least some of the inhibitory effects previously ascribed to the membrane-bound isoform. These results suggest that the immune system exploits the different CTLA-4 isoforms for either intrinsic or extrinsic regulation of T-cell activity. Keywords: CD4 + T cells r Costimulatory molecules r Immune regulation r Treg cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site Introduction CTLA-4 is an important regulator of T-cell responses [1][2][3][4]. Its critical role is highlighted by CTLA-4 knockout mice, which develop a fatal lymphoproliferative disorder soon after birth, arising from a profound failure of T-cell homeostasis [5,6]. Despite these potent effects, the activities of CTLA-4 are only partially understood.CTLA-4 shares sequence homology and B7 ligands (CD80/CD86) with the costimulatory molecule, CD28, but differs by delivering inhibitory, rather than activating, signals to the T cells on which it is expressed as a receptor [7,8]. Upregulation of CTLA-4 on activated T cells provides a mechanism for negative Correspondence: Dr. Frank J. Ward e-mail: mmd475@abdn.ac.uk feedback to control their responses. However, not all its regulatory effects are explained by inhibitory costimulation, since CTLA-4 can also suppress activated effector T-cell populations without the need for them to express it [9,10]. This latter, cell-extrinsic mechanism has been largely attributed to CD4 + regulatory T (Treg)-cell subsets, which constitutively express high levels of CTLA-4, and require it for their regulatory function [11][12][13][14][15][16].How Treg cells might use CTLA-4 to regulate effector T-cell responses remains controversial. It has been suggested that CTLA-4 on Treg cells binds B7 and thus blocks CD28-mediated effector T-cell costimulation, or that it induces inhibitory mechanisms in the APC such as the IDO tryptophan catabolic enzyme * These authors contributed equally to this work.www.eji-journal.eu Eur. J. Immunol. 2013. 43: 1274-1285 Immunomodulation 1275 cas...

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Section: Abstract: Cd4 + T Cells R Costimulatory Molecules R Immune Rmentioning

confidence: 99%

The soluble isoform of CTLA‐4 as a regulator of T‐cell responses

et al. 2013

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“…The discovery of CD4 þ Foxp3 þ Tregs that express high levels of CTLA-4 on their surface, however, suggested a different cellular target for the a-CTLA-4 antibodies-the Tregs themselves (7,8). More recent studies have shown that the blockade of CTLA-4 on both T-effector cells and Tregs is required for optimal tumor immunity (9), and at least in cases in which tumors contain large numbers of macrophages that express Fcg receptors, a-CTLA-4 antibodies seem to mediate the specific depletion of tumor-infiltrating Tregs via an Fc-dependent mechanism (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic T Lymphocyte Antigen-4 Blockade Enhances Antitumor Immunity by Stimulating Melanoma-Specific T-cell Motility

Pentcheva-Hoang

Simpson

Montalvo-Ortiz

et al. 2014

Cancer Immunology Research

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It is now clear that anti-CTLA-4 (a-CTLA-4) antibodies stimulate tumor immunity either by relieving inhibition of effector T-cell function or by depletion of regulatory T cells (Treg). Several recent reports, however, have suggested that these antibodies may deliver a "go" signal to effector T cells, thus interrupting T-cell receptor signaling and subsequent T-cell activation. We examined the behavior of melanoma-specific CD8 þ pmel-1 T cells in the B16/BL6 mouse model using intravital microscopy. Pmel-1 velocities in progressively growing tumors were lower than their velocities in tumors given a therapeutic combination that included a-CTLA-4 antibodies, suggesting that successful immunotherapy correlates with greater T-cell motility. When a-CTLA-4 antibodies were injected during imaging, the velocities of pmel-1 T cells in tumor-draining lymph nodes also increased. Because a-CTLA-4 Fab fragments had the same effect as the intact antibody, the higher T-cell motility does not seem to be due to CTLA-4 inhibitory signaling but rather to the release of nonproductive stable interactions between tumor-infiltrating T cells and tumor targets or antigen-presenting cells subsequent to CTLA-4 blockade. This phenomenon resembles the recently described reversal of the antiviral T-cell motility paralysis by programmed death 1 (PD-1)-specific antibodies during T-cell exhaustion in persistent viral infections. Cancer Immunol Res; 2(10); 970-80. Ó2014 AACR.

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“…15,16 Moreover, evidences of modification of the balance between effector and regulatory immune responses, involving myeloid derived suppressor cells (MDSCs) and regulatory T cells (Treg), both in the circulation and in tumor infiltrates were reported in association with the clinical activity of IPI. 2,17,18 Along this line, the increase of the absolute leukocyte cell count (ALC) or of circulating CD4 C T cells expressing the inducible co-stimulatory molecule (ICOS) have been documented in relation with anti-CTLA-4 mAb therapies. 12,[19][20][21] ICOS C T cells that were augmented by IPI therapy in tumor lesions from prostate cancer patients, represented lymphocytes endowed with antitumor activity.…”

Section: Introductionmentioning

confidence: 99%

“…1,2 These agents showed durable clinical benefit and increased OS, 3,4 for patients with advanced melanoma. Since then, the usage of anti-CTLA-4 mAbs (either ipilimumab, IPI or tremelimumab) in several clinical studies or in the context of expanded access programs (EAP) has shown significant increase in OS for MM patients, and promising clinical activity for tumors with other histology.…”

Section: Introductionmentioning

confidence: 99%

Immunological markers and clinical outcome of advanced melanoma patients receiving ipilimumab plus fotemustine in the NIBIT-M1 study

Maccalli

Giannarelli²,

Capocefalo³

et al. 2015

OncoImmunology

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Moreover, either the absence or the presence of soluble NKG2D ligands (ULBP-1 or ¡2) at baseline in the serum of MM patients enabled to discriminate subjects with long-term survival (median overall survival, (OS) D 33.6 mo for ULBP-1 and ¡2) from poor survivors (OS D 9.8 or 6.6 mo, respectively). Conversely, no significant association between the levels of soluble MICA, MICB and ULBP-3 and the clinical outcome of patients was observed. An inverse correlation between circulating levels of these molecules at baseline and frequency of either CD3 C CD4 C CD45RO C BTLA C or Th17 or CD3 C CD4 C 4-1BB C T cells occurred in patients with a favorable clinical outcome. The simultaneous monitoring of different immune parameters, though validation in a large cohort of patients is needed, allowed to identify an association between phenotypic and soluble markers representing a possible predictive immunological signature for the clinical activity of IPI plus FTM.

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Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti–CTLA-4 antibodies

Cited by 832 publications

References 36 publications

The soluble isoform of CTLA‐4 as a regulator of T‐cell responses

The soluble isoform of CTLA‐4 as a regulator of T‐cell responses

Cytotoxic T Lymphocyte Antigen-4 Blockade Enhances Antitumor Immunity by Stimulating Melanoma-Specific T-cell Motility

Immunological markers and clinical outcome of advanced melanoma patients receiving ipilimumab plus fotemustine in the NIBIT-M1 study

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