Vascular Endothelial Growth Factor-D–Mediated Blockade of Regulatory T Cells within Tumors Is Induced by Hematopoietic Stem Cell Transplantation

Udagawa, Tsuyoshi; Narumi, Kenta; Suzuki, Kôji; Aida, Kouichirou; Miyakawa, Reina; Ikarashi, Yoshinori; Makimoto, Atsushi; Chikaraishi, Tatsuya; Yoshida, Teruhiko; Aoki, Kazunori

doi:10.4049/jimmunol.1201454

Cited by 5 publications

(7 citation statements)

References 46 publications

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“…1A left). Tumor growth was significantly suppressed in the HSCT recipients as previously reported [10,11]. The tumor growth suppression was largely cancelled by the depletion of NK cells ( Fig.…”

Section: Nk Cells Undergoing Hp Resulted In An Antitumor Effect Aftersupporting

confidence: 90%

“…It has been reported that the immune reconstitution of autologous HSCT recipients is responsible for improved T‐cell priming and antitumor efficacy . In addition, we recently found that vascular endothelial growth factor (VEGF)‐D‐mediated suppression of Tregs in tumor is important for inducing an effective antitumor immunity after syngeneic HSCT . Except for these two T cell‐mediated mechanisms, the role of NK cells in inducing antitumor immunity has not been elucidated because T cells have been considered as the most important and potent immune cells involved in antitumor immunity.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we recently found that the frequency of CD4 + T cells expressing Foxp3 was significantly decreased in the tumor but not in the spleen after HSCT and that the decrease in Tregs was dependent on interleukin-6 (IL-6) produced by dendritic cells in the tumor. The results indicate that autologous HSCT creates an environment strongly supporting antitumor immunity in reconstituted lymphopenic recipients [10,11]. However, the mechanisms of antitumor immunity induced by the autologous HSCT are not fully understood.…”

Section: Original Researchmentioning

confidence: 99%

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Interaction of natural killer cells with neutrophils exerts a significant antitumor immunity in hematopoietic stem cell transplantation recipients

Ueda¹,

Narumi²,

Hashimoto³

et al. 2015

Cancer Medicine

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Autologous hematopoietic stem cell transplantation (HSCT) can induce a strong antitumor immunity by homeostatic proliferation (HP) of T cells and suppression of regulatory T cells following preconditioning‐induced lymphopenia. However, the role of innate immunity including natural killer (NK) cells is still not understood. Here, first, we examined whether NK cells exert an antitumor effect after syngeneic HSCT in a murine colon cancer model. Flow cytometry showed that NK cells as well as T cells rapidly proliferated after HSCT, and the frequency of mature NK cells was increased in tumor during HP. Furthermore, NK cells undergoing HP were highly activated, which contributed to substantial tumor suppression. Then, we found that a large number of neutrophils accumulated in tumor early after syngeneic HSCT. It was recently reported that neutrophil‐derived mediators modulate NK cell effector functions, and so we examined whether the neutrophils infiltrated in tumor are associated with NK cell‐mediated antitumor effect. The depletion of neutrophils significantly impaired an activation of NK cells in tumor and increased the fraction of proliferative NK cells accompanied by a decrease in NK cell survival. The results suggested that neutrophils in tumor prevent NK cells from activation‐induced cell death during HP, thus leading to a significant antitumor effect by NK cells. This study revealed a novel aspect of antitumor immunity induced by HSCT and may contribute to the development of an effective therapeutic strategy for cancer using HSCT.

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Section: Nk Cells Undergoing Hp Resulted In An Antitumor Effect Aftersupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Original Researchmentioning

confidence: 99%

See 1 more Smart Citation

Interaction of natural killer cells with neutrophils exerts a significant antitumor immunity in hematopoietic stem cell transplantation recipients

Ueda¹,

Narumi²,

Hashimoto³

et al. 2015

Cancer Medicine

Self Cite

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“…Interestingly, a recent study showed that VEGF-D induces and a VEGFR-3 neutralizing antibody suppresses the production of IL-6 by CD11c + dendritic cells and results in enhanced anti-tumor immunity in an allogeneic hematopoietic stem cell transplantation model in mice, thus endorsing our view about the immunomodulative role of the VEGF-D/VEGFR-3 axis [50] . Moreover, transgenic delivery of VEGF-C or VEGF-D was shown to ameliorate the persistent chronic inflammation in the oxazolone-treated skin of K14-VEGF-A mice, implying that functional lymphatic vessels activation via VEGFR-3 functions in preventing the development of chronic inflammation [51] .…”

Section: Discussionmentioning

confidence: 84%

Elevated VEGF-D Modulates Tumor Inflammation and Reduces the Growth of Carcinogen-Induced Skin Tumors

et al. 2016

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Vascular endothelial growth factor D (VEGF-D) promotes the lymph node metastasis of cancer by inducing the growth of lymphatic vasculature, but its specific roles in tumorigenesis have not been elucidated. We monitored the effects of VEGF-D in cutaneous squamous cell carcinoma (cSCC) by subjecting transgenic mice overexpressing VEGF-D in the skin (K14-mVEGF-D) and VEGF-D knockout mice to a chemical skin carcinogenesis protocol involving 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate treatments. In K14-mVEGF-D mice, tumor lymphangiogenesis was significantly increased and the frequency of lymph node metastasis was elevated in comparison with controls. Most notably, the papillomas regressed more often in K14-mVEGF-D mice than in littermate controls, resulting in a delay in tumor incidence and a remarkable reduction in the total tumor number. Skin tumor growth and metastasis were not obviously affected in the absence of VEGF-D; however, the knockout mice showed a trend for reduced lymphangiogenesis in skin tumors and in the untreated skin. Interestingly, K14-mVEGF-D mice showed an altered immune response in skin tumors. This consisted of the reduced accumulation of macrophages, mast cells, and CD4+ T-cells and an increase of cytotoxic CD8+ T-cells. Cytokine profiling by flow cytometry and quantitative real time PCR revealed that elevated VEGF-D expression results in an attenuated Th2 response and promotes M1/Th1 and Th17 polarization in the early stage of skin carcinogenesis, leading to an anti-tumoral immune environment and the regression of primary tumors. Our data suggest that VEGF-D may be beneficial in early-stage tumors since it suppresses the pro-tumorigenic inflammation, while at later stages VEGF-D-induced tumor lymphatics provide a route for metastasis.

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“… also reported that the transplantation increases the ratio of effector T cells/regulatory T cells in the transferred splenocytes, due to the synergistic effect of the HP combined with encountering their cognate antigen in tumor‐bearing mice. In addition, we recently found that HSCT significantly decreased the frequency of Tregs per CD4 + T cells in the tumors but not in the spleens, and that the blockade of Tregs was dependent on IL‐6 produced by DCs in the tumors . The break of regional immune tolerance within tumors may be another mechanism of an antitumor immunity of HSCT.…”

Section: Discussionmentioning

confidence: 97%

Preimmunization of donor lymphocytes enhances antitumor immunity of autologous hematopoietic stem cell transplantation

Suzuki

Aida²,

Miyakawa³

et al. 2013

Cancer Medicine

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Lymphopenia-induced homeostatic proliferation (HP) of T cells following autologous hematopoietic stem cell transplantation (HSCT) skews the T-cell repertoire by engaging tumor-associated antigens (TAAs), leading to an induction of antitumor immunity. Here, as the tumor-reactive lymphocytes preferentially proliferate during the condition of HP, we examined whether the priming of a donor lymphocytes to TAAs could enhance HP-induced antitumor immunity in autologous HSCT recipients. First, to examine whether the tumor-bearing condition of donor influences the antitumor effect of HSCT, the lymphocytes isolated from CT26 tumor-bearing mice were infused into lethally irradiated mice. The growth of tumors was substantially suppressed in the mice that received HSCT from a tumor-bearing donor compared with a naïve donor, suggesting that a fraction of donor lymphocytes from tumor-bearing mice are primed in response to TAAs and remain responsive upon transplantation. We previously reported that type I interferon (IFN) maturates the dendritic cells and promotes the priming of T cells. We then investigated whether the further priming of donor cells by IFN-α can strengthen the antitumor effect of HSCT. The intratumoral IFN-α gene transfer significantly increased the number of IFN-γ-positive lymphocytes in response to CT26 cells but not the syngeneic lymphocytes in donor mice. The infusion of primed donor lymphocytes markedly suppressed the tumor growth in recipient mice, and cured 64% of the treated mice. Autologous HSCT with the infusion of primed donor lymphocytes is a promising strategy to induce an effective antitumor immunity for solid cancers.

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Vascular Endothelial Growth Factor-D–Mediated Blockade of Regulatory T Cells within Tumors Is Induced by Hematopoietic Stem Cell Transplantation

Cited by 5 publications

References 46 publications

Interaction of natural killer cells with neutrophils exerts a significant antitumor immunity in hematopoietic stem cell transplantation recipients

Interaction of natural killer cells with neutrophils exerts a significant antitumor immunity in hematopoietic stem cell transplantation recipients

Elevated VEGF-D Modulates Tumor Inflammation and Reduces the Growth of Carcinogen-Induced Skin Tumors

Preimmunization of donor lymphocytes enhances antitumor immunity of autologous hematopoietic stem cell transplantation

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