Journal Article
. 2010 Oct; 70(20):7788-99.
doi: 10.1158/0008-5472.CAN-10-1736.

Selective depletion of Foxp3+ regulatory T cells improves effective therapeutic vaccination against established melanoma

Katjana Klages 1 Christian T Mayer  Katharina Lahl  Christoph Loddenkemper  Michele W L Teng  Shin Foong Ngiow  Mark J Smyth  Alf Hamann  Jochen Huehn  Tim Sparwasser  
Affiliations
  • PMID: 20924102
  •     121 citations

Abstract

Tumor-bearing individuals have been reported to harbor increased numbers of Foxp3(+) regulatory T cells (Treg), which prevent the development of efficient antitumor immune responses. Thus, Treg depletion has already been tested as a promising therapeutic approach in various animal models and entered clinical trials. However, the use of nonspecific Treg targeting agents such as CD25 depleting antibodies, which in addition to CD25(+) Tregs also deplete recently activated CD25(+) effector T cells, potentially masked the tremendous potential of this therapeutic strategy. To avoid such nonspecific effects, we used transgenic DEREG (depletion of regulatory T cells) mice, which express a diphtheria toxin receptor under control of the Foxp3 locus, allowing selective depletion of Foxp3(+) Tregs even during ongoing immune responses. We showed that Foxp3(+) Treg depletion induced partial regression of established ovalbumin (OVA)-expressing B16 melanoma, which was associated with an increased intratumoral accumulation of activated CD8(+) cytotoxic T cells. The antitumor effect could be significantly enhanced when Treg depletion was combined with vaccination against OVA. To further assess whether this therapeutic approach would break self-tolerance, we crossed DEREG mice with RipOVA(low) mice, expressing OVA as neo-self-antigen under control of the rat insulin promoter. In these mice, combined Treg depletion and vaccination also induced tumor regression without the onset of diabetes. Together, our data suggest that selective Treg targeting strategies combined with vaccinations against tumor-associated (self) antigens have the potential to evoke efficient antitumor responses without inducing overt autoimmunity. These findings might have implications for future therapeutic interventions in cancer patients.

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Therapeutic depletion of CCR8+ tumor-infiltrating regulatory T cells elicits antitumor immunity and synergizes with anti-PD-1 therapy.
Helena Van Damme, Bruno Dombrecht, +26 authors, Jo Agnes Van Ginderachter.
J Immunother Cancer, 2021 Feb 17; 9(2). PMID: 33589525    Free PMC article.
Critical Roles of Balanced T Helper 9 Cells and Regulatory T Cells in Allergic Airway Inflammation and Tumor Immunity.
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J Immunol Res, 2021 Mar 23; 2021. PMID: 33748292    Free PMC article.
Review.
Foxp3 Silencing with Antisense Oligonucleotide Improves Immunogenicity of an Adjuvanted Recombinant Vaccine against Sporothrix schenckii.
Alexander Batista-Duharte, Luis Sendra, +10 authors, Salvador Francisco Aliño.
Int J Mol Sci, 2021 Apr 04; 22(7). PMID: 33801683    Free PMC article.
Targeting the epigenetic regulation of antitumour immunity.
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Nat Rev Drug Discov, 2020 Sep 16; 19(11). PMID: 32929243
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Immune checkpoint blockade impairs immunosuppressive mechanisms of regulatory T cells in B-cell lymphoma.
Vera Bauer, Fatima Ahmetlić, +3 authors, Ralph Mocikat.
Transl Oncol, 2021 Jul 07; 14(9). PMID: 34229208    Free PMC article.
Interleukin-10: A double-edged sword in breast cancer.
Chun-Ming Chang, Ho Yin Pekkle Lam, Hao-Jen Hsu, Shinn-Jong Jiang.
Tzu Chi Med J, 2021 Aug 14; 33(3). PMID: 34386356    Free PMC article.
Review.
Cytotoxic CD8+ T cell ablation enhances the capacity of regulatory T cells to delay viral elimination in Theiler's murine encephalomyelitis.
Malgorzata Ciurkiewicz, Vanessa Herder, +6 authors, Andreas Beineke.
Brain Pathol, 2017 Apr 30; 28(3). PMID: 28452087    Free PMC article.
The TNF-α/TNFR2 Pathway: Targeting a Brake to Release the Anti-tumor Immune Response.
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Front Cell Dev Biol, 2021 Oct 30; 9. PMID: 34712661    Free PMC article.
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Tumor-derived extracellular vesicles regulate tumor-infiltrating regulatory T cells via the inhibitory immunoreceptor CD300a.
Yuta Nakazawa, Nanako Nishiyama, +3 authors, Akira Shibuya.
Elife, 2021 Nov 10; 10. PMID: 34751648    Free PMC article.
Chemogenetic modulation of sensory neurons reveals their regulating role in melanoma progression.
Pedro A C Costa, Walison N Silva, +15 authors, Alexander Birbrair.
Acta Neuropathol Commun, 2021 Nov 18; 9(1). PMID: 34784974    Free PMC article.
Remodeling of the tumor microenvironment via disrupting Blimp1+ effector Treg activity augments response to anti-PD-1 blockade.
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Mol Cancer, 2021 Nov 21; 20(1). PMID: 34798898    Free PMC article.
Pushing Past the Blockade: Advancements in T Cell-Based Cancer Immunotherapies.
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Front Immunol, 2021 Dec 07; 12. PMID: 34868044    Free PMC article.
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Current Perspectives on the Immunosuppressive Niche and Role of Fibrosis in Hepatocellular Carcinoma and the Development of Antitumor Immunity.
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J Histochem Cytochem, 2021 Nov 10; 70(1). PMID: 34751050    Free PMC article.
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CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory.
Yujiro Kidani, Wataru Nogami, +39 authors, Shimon Sakaguchi.
Proc Natl Acad Sci U S A, 2022 Feb 11; 119(7). PMID: 35140181    Free PMC article.
PD-L1 signaling selectively regulates T cell lymphatic transendothelial migration.
Wenji Piao, Lushen Li, +12 authors, Jonathan S Bromberg.
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Direct targeting of FOXP3 in Tregs with AZD8701, a novel antisense oligonucleotide to relieve immunosuppression in cancer.
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J Immunother Cancer, 2022 Apr 08; 10(4). PMID: 35387780    Free PMC article.
Innate Lymphoid Cells: Role in Immune Regulation and Cancer.
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Cancers (Basel), 2022 May 15; 14(9). PMID: 35565201    Free PMC article.
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