Treg Depletion Inhibits Efficacy of Cancer Immunotherapy: Implications for Clinical Trials

Curtin, James F.; Candolfi, Marianela; Fakhouri, Tamer; Liu, Chunyan; Alden, Anderson; Edwards, Matthew R.; Löwenstein, Pedro R.; Castro, María G.

doi:10.1371/journal.pone.0001983

Cited by 108 publications

(125 citation statements)

References 48 publications

(75 reference statements)

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“…These data are consistent with previous work from our group indicating that combined use of Flt3L + TK (+ ganciclovir) to treat unilateral intracranial brain tumors induces an effective anti-brain-tumor immune response without overt autoimmunity (37)(38)(39)(40)(41)(42), and the data strongly support the addition of Flt3L as an adjuvant to cytotoxic and immunostimulatory approaches currently under evaluation for the treatment of human malignant brain tumors.…”

Section: Discussionsupporting

confidence: 91%

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Exogenous fms-like tyrosine kinase 3 ligand overrides brain immune privilege and facilitates recognition of a neo-antigen without causing autoimmune neuropathology

Larocque¹,

Sanderson²,

Bergeron³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Soluble antigens diffuse out of the brain and can thus stimulate a systemic immune response, whereas particulate antigens (from infectious agents or tumor cells) remain within brain tissue, thus failing to stimulate a systemic immune response. Immune privilege describes how the immune system responds to particulate antigens localized selectively within the brain parenchyma. We believe this immune privilege is caused by the absence of antigen presenting dendritic cells from the brain. We tested the prediction that expression of fms-like tyrosine kinase ligand 3 (Flt3L) in the brain will recruit dendritic cells and induce a systemic immune response against exogenous influenza hemagglutinin in BALB/c mice. Coexpression of Flt3L with HA in the brain parenchyma induced a robust systemic anti-HA immune response, and a small response against myelin basic protein and proteolipid protein epitopes. Depletion of CD4 + CD25+ regulatory T cells (Tregs) enhanced both responses. To investigate the autoimmune impact of these immune responses, we characterized the neuropathological and behavioral consequences of intraparenchymal injections of Flt3L and HA in BALB/c and C57BL/6 mice. T cell infiltration in the forebrain was time and strain dependent, and increased in animals treated with Flt3L and depleted of Tregs; however, we failed to detect widespread defects in myelination throughout the forebrain or spinal cord. Results of behavioral tests were all normal. These results demonstrate that Flt3L overcomes the brain's immune privilege, and supports the clinical development of Flt3L as an adjuvant to stimulate clinically effective immune responses against brain neo-antigens, for example, those associated with brain tumors.immune response | dendritic cells | influenza hemagglutinin | regulatory T cells | perivascular cuffs

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Section: Discussionsupporting

confidence: 91%

“…To deplete CD25 + Tregs, mice were treated with a single i.p. injection of 1 mg ascites fluid (600 μL) from the PC61 hybridoma (41). Results of a pilot experiment confirming depletion of Foxp3+, CD25+ Tregs after PC-61 treatment are shown in …”

Section: Methodsmentioning

confidence: 88%

Exogenous fms-like tyrosine kinase 3 ligand overrides brain immune privilege and facilitates recognition of a neo-antigen without causing autoimmune neuropathology

Larocque¹,

Sanderson²,

Bergeron³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Remarkably, both adjuvant therapies depleted not only Treg, as previously described (30,47,48), but also Mo-MDSC. In part, this can be explained by the fact that anti-CD25 mAb targets IL-2Ra, expressed in many immune cell subsets, including tumor monocyte-derived dendritic cells (49).…”

Section: Discussionsupporting

confidence: 64%

Successful Colon Cancer Eradication after Chemoimmunotherapy Is Associated with Profound Phenotypic Change of Intratumoral Myeloid Cells

Medina-Echeverz

Fioravanti

Zabala

et al. 2011

The Journal of Immunology

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IL-12 is a potent immunostimulatory cytokine, but its impact as an antitumor drug in clinical practice is limited. Upsurge of regulatory T cells (Treg) in the tumor milieu has been proposed to limit the efficacy of the treatment. In this paper, two drugs (cyclophosphamide [CPA] and anti-CD25 mAb) widely used to eliminate Treg were used in an attempt to enhance the antitumor effect of IL-12 gene therapy. Both anti-CD25 and CPA combined with IL-12 were able to deplete intratumoral Treg and myeloid-derived suppressor cells (MDSC), but only IL-12 plus CPA achieved significant antitumor activity in mice with large established s.c. colon carcinoma. This therapeutic effect was associated with the emergence of a heterogeneous population of myeloid cells within the tumor, termed inflammatory myeloid cells (IMC), composed of Ly6ChighLy6Glow inflammatory monocytes and Ly6GhighLy6C+ neutrophils. IMC showed a distinctive pattern of cytokine/chemokine production, and in contrast to MDSC, they did not induce conversion of naive CD4+ T cells into Treg. The appearance of IMC coincided with intense tumor infiltration by effector T cells, which was abrogated by elimination of IMC by anti-Gr1 mAb, a maneuver that abolished the antitumor effect of the therapy. Therefore, the combination of IL-12 and CPA eliminates intratumoral Treg and MDSC, while it induces the appearance of IMC within the tumor microenvironment. The latter effect is essential to facilitate effector T cell infiltration and subsequent tumor elimination.

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“…Because we show that daclizumab depletes all CD25 high lymphocytes in vivo, daclizumab may partly neutralize this pre-existing antitumor immune response. A similar hypothesis was raised by Curtin et al to explain why anti-CD25 mAb in a mouse glioblastoma model can eliminate newly induced tumors but cannot inhibit tumor progression in established tumors (47). Thirdly, in all patients that received a single dose of 0.5 mg/kg daclizumab, the drug was still present during subsequent dendritic cell vaccinations.…”

Section: Discussionmentioning

confidence: 68%

Dendritic Cell Vaccination in Combination with Anti-CD25 Monoclonal Antibody Treatment: A Phase I/II Study in Metastatic Melanoma Patients

Jacobs

Punt

Lesterhuis

et al. 2010

Clinical Cancer Research

215

175

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Purpose: The success of cancer immunotherapy depends on the balance between effector T cells and suppressive immune regulatory mechanisms within the tumor microenvironment. In this study we investigated whether transient monoclonal antibody-mediated depletion of CD25 high regulatory T cells (Treg) is capable of enhancing the immunostimulatory efficacy of dendritic cell vaccines.Experimental Design: Thirty HLA-A2.1 + metastatic melanoma patients were vaccinated with mature dendritic cells pulsed with tumor peptide and keyhole limpet hemocyanin (KLH). Half of the patients were pretreated with daclizumab, a humanized antibody against the interleukin-2 (IL-2) receptor α-chain (CD25), either four or eight days before dendritic cell vaccinations. Clinical and immunologic parameters were determined.Results: Daclizumab efficiently depleted all CD25 high immune cells, including CD4 + FoxP3 + CD25 high cells, from the peripheral blood within four days of administration. Thirty days after administration, daclizumab was cleared from the circulation and all CD25 + cells reappeared. The presence of daclizumab during dendritic cell vaccinations prevented the induction of specific antibodies in vivo but not the presence of antigen-specific T cells. Daclizumab, however, did prevent these CD25 + T cells from acquiring effector functions. Consequently, significantly less patients pretreated with daclizumab developed functional, vaccine-specific effector T cells and antibodies compared with controls. Daclizumab pretreatment had no significant effect on progression-free survival compared with the control group.Conclusions: Although daclizumab depleted the CD4 + FoxP3 + CD25 high Tregs from the peripheral circulation, it did not enhance the efficacy of the dendritic cell vaccine. Residual daclizumab functionally suppressed de novo induced CD25 + effector cells during dendritic cell vaccinations. Our results indicate that for immunotherapeutic benefit of transient Treg depletion, timing and dosing as well as Treg specificity are extremely important. Clin Cancer Res; 16(20); 5067-78. ©2010 AACR.Melanoma is considered one of the most immunogenic types of cancers. This is based on the following arguments: (a) several melanoma-specific antigens have been identified (1, 2); (b) functional lymphocytes specific for melanoma antigens are increased in melanoma patients (3); (c) immune-stimulating agents can have a positive effect on disease outcome (4, 5); and (d) spontaneous melanoma regressions with simultaneous onset of vitiligo have been reported (6).Immunotherapeutic clinical trials have succeeded in expanding melanoma-specific effector T cells in vivo, but favorable outcomes are still limited because tumor-induced mechanisms of immune evasion may render the host tolerant for melanoma antigens (7,8). Immunosuppression at the tumor microenvironment mediated by regulatory T cells (Treg) is one of the most critical mechanisms of tumor-immune escape and a major hurdle for successful immunotherapy (9-11).In melanoma patients, selective...

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Treg Depletion Inhibits Efficacy of Cancer Immunotherapy: Implications for Clinical Trials

Cited by 108 publications

References 48 publications

Exogenous fms-like tyrosine kinase 3 ligand overrides brain immune privilege and facilitates recognition of a neo-antigen without causing autoimmune neuropathology

Exogenous fms-like tyrosine kinase 3 ligand overrides brain immune privilege and facilitates recognition of a neo-antigen without causing autoimmune neuropathology

Successful Colon Cancer Eradication after Chemoimmunotherapy Is Associated with Profound Phenotypic Change of Intratumoral Myeloid Cells

Dendritic Cell Vaccination in Combination with Anti-CD25 Monoclonal Antibody Treatment: A Phase I/II Study in Metastatic Melanoma Patients

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