Depletion of radio-resistant regulatory T cells enhances antitumor immunity during recovery from lymphopenia

Baba, Junko; Watanabe, Satoshi; Saida, Yu; Tanaka, Tomohiro; Miyabayashi, Takao; Koshio, Jun; Ichikawa, Kosuke; Nozaki, Kohei; Koya, Toshiyuki; Deguchi, Katsuya; Tan, Chunrui; Miura, Satoru; Tanaka, Hiroshi; Tanaka, Junta; Kagamu, Hiroshi; Yoshizawa, Hirohisa; Nakata, Katsuhiko; Narita, Ichiei

doi:10.1182/blood-2012-02-411124

Cited by 61 publications

(49 citation statements)

References 39 publications

(43 reference statements)

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“…64 The latter is supported by the observation that depletion of regulatory T cells potentiates the anti-neoplastic effect of RT in murine models. 54,64,65 Interestingly, beside X-or g-irradiation, vaccination with a-irradiated (bismuth-213) murine adenocarcinoma MC-38 also induces long-lasting protective antitumor Immunopotentiating effects of cyclophosphamide are highly dose dependent in both humans as well as preclinical animal models. Metronomic doses of cyclophoshamide have been found to be "ICD-supportive" however high doses can be strongly immunosuppressive.…”

Section: Physical Modalities Inducing Tumor Immunogenicitymentioning

confidence: 99%

Physical modalities inducing immunogenic tumor cell death for cancer immunotherapy

et al. 2014

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Section: Physical Modalities Inducing Tumor Immunogenicitymentioning

confidence: 99%

Physical modalities inducing immunogenic tumor cell death for cancer immunotherapy

et al. 2014

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“…Hence, it is possible that by removing tumor-specific Tregs, antitumor immunity could be enhanced. Many studies in mice have shown that removal or inhibition of this subset of cells can enhance antitumor immune responses (30,31). Decreasing immunosuppressive cytokines by depleting tumor infiltrating Tregs by combining DCs and anti-GITR Abs could represent an important adjunct to cancer immunotherapy.…”

Section: Foxp3mentioning

confidence: 99%

Dendritic cells combined with anti-GITR antibody produce antitumor effects in osteosarcoma

et al. 2015

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Abstract. We attempted to enhance the antitumor effects of tumor lysate-pulsed dendritic cells by eliminating regulatory T cells. The combinatorial effects of dendritic cells and agonist anti-glucocorticoid-induced tumor necrosis factor receptor (anti-GITR) antibodies were investigated with respect to enhancement of the systemic immune response, elimination of regulatory T cells, and inhibition of tumor growth. To determine whether the combination of dendritic cells and anti-GITR antibodies could enhance systemic immune responses and inhibit primary tumor growth in a murine osteosarcoma (LM8) model. We established the following 4 groups of C3H mice (20 mice in total): i), control IgG-treated mice; ii), tumor lysate-pulsed dendritic cell-treated mice; iii), agonist anti-GITR antibody-treated mice; and iv), agonist anti-GITR antibody-and tumor lysate-pulsed dendritic cell-treated mice. The mice that received the agonist anti-GITR antibodies and tumor lysate-pulsed dendritic cells displayed inhibited primary growth, prolonged life time, reduced numbers of regulatory T lymphocytes in the spleen, elevated serum interferon-γ levels, increased number of CD8 + T lymphocytes. The mice that received combined therapy had reduced level of immunosuppressive cytokines in tumor tissue and serum. Combining agonist anti-GITR antibodies with tumor lysate-pulsed dendritic cells enhanced the systemic immune response. These findings provide further support for the continued development of agonist anti-GITR antibodies as an immunotherapeutic strategy for osteosarcoma. We suggest that our proposed immunotherapy could be developed further to improve osteosarcoma treatment.

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“…9 Therefore, blockade the TNF-a/TNFR2 signaling could possibly prevent the re-expansion of Treg cells after irradiation and/or cyclophosphamide treatment. Mice with CT26 were treated with cyclophosphamide and decreased numbers of CD4 C Foxp3 ¡ and CD8 C T cells were found in the spleen and tumor draining lymph node (DLN) (Figs.…”

Section: Blockade Of Tnf-a/tnfr2 Signaling Inhibits Effector Treg Celmentioning

confidence: 99%

“…The rapid recovery of Treg cells after lymphodepletion is reported as main reason of treatment failure due to inhibition of antitumor immune responses by these recovered Treg cells. 9 Though these Treg cells could be depleted with anti-CD25 mAb, the increased risk of inducing severe autoimmune disease is high due to depletion of all endogenous Treg cells. 9 Here, we provide another tumor immunotherapeutic strategy by targeting only effector Treg cells but not all Treg cells through TNF-a inhibitors to efficiently diminish the expansion of effector Treg cells after lymphodepletion.…”

Section: E1040215-8 Volume 4 Issue 10 Oncoimmunologymentioning

confidence: 99%

Blockade of TNF-α signaling benefits cancer therapy by suppressing effector regulatory T cell expansion

et al. 2015

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Effector but not naive regulatory T cells (Treg cells) can accumulate in the peripheral blood as well as the tumor microenvironment, expand during tumor progression and be one of the main suppressors for antitumor immunity. However, the underlying mechanisms for effector Treg cell expansion in tumor are still unknown. We demonstrate that effector Treg cell-mediated suppression of antitumor CD8C T cells is tumor-nonspecific. Furthermore, TNFR2 expression is increased in these Treg cells by Affymetrix chip analysis which was confirmed by monoclonal antibody staining in both hepatocellular carcinoma (HCC) and colorectal cancer (CRC) patients and murine models. Correspondingly, increased levels of TNF-a in both tissue and serum were also demonstrated. Interestingly, TNF-a could not only expand effector Treg cells through TNFR2 signaling, but also enhanced their suppressive activity against antitumor immunity of CD8 C T cells. Furthermore, targeting TNFR2 signaling with a TNF-a inhibitor could selectively reduce rapid resurgence of effector Treg cells after cyclophosphamide-induced lymphodepletion and markedly inhibit the growth of established tumors. Herein, we propose a novel mechanism in which TNF-a could promote tumor-associated effector Treg cell expansion and suggest a new cancer immunotherapy strategy using TNF-a inhibitors to reduce effector Treg cells expansion after cyclophosphamide-induced lymphodepletion.

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Depletion of radio-resistant regulatory T cells enhances antitumor immunity during recovery from lymphopenia

Cited by 61 publications

References 39 publications

Physical modalities inducing immunogenic tumor cell death for cancer immunotherapy

Physical modalities inducing immunogenic tumor cell death for cancer immunotherapy

Dendritic cells combined with anti-GITR antibody produce antitumor effects in osteosarcoma

Blockade of TNF-α signaling benefits cancer therapy by suppressing effector regulatory T cell expansion

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