Distinct Role of Antigen-Specific T Helper Type 1 (Th1) and Th2 Cells in Tumor Eradication in Vivo

Nishimura, Takashi; Iwakabe, Kenji; Sekimoto, Miho; Ohmi, Yasushi; Yahata, Takashi; Nakui, Minoru; Sato, Takehito; Habu, Sonoko; Tashiro, Hiroyuki; Sato, Masamitsu; Ohta, Akio

doi:10.1084/jem.190.5.617

Cited by 401 publications

(413 citation statements)

References 43 publications

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“…Thus, our results indicate that IL-17-producing gd T cells act as pro-but not anti-tumor effector cells in tumorgrowing microenvironment. In our previous work [16][17][18][19][20], we have proposed that the introduction of Th1-dominant immunity overcomes strong immunosuppression in tumor-bearing host and induces complete cure of the tumor-bearing mice. Therefore, we now investigated whether Th1 cell therapy or introduction of Th1 immunity by IL-12 can induce a plasticity in IL-17-producing gd T cells, namely, alter pro-to anti-tumor IL-17-producing gd T cells.…”

Section: Discussionmentioning

confidence: 99%

“…We have proposed that the induction of Th1-dominant immune responses is an essential step in inducing strong anti-tumor immunity in response to adjuvants or tumor-specific Th1 cells [16][17][18][19][20]. However, within the tumor microenvironment, the balance between IL-12 and IL-23, which directly reflects Th1 and Th17 cell responses, is shifted toward IL-23 via activation of STAT3 [21,22].…”

Section: Introductionmentioning

confidence: 99%

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Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis

et al. 2010

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Based on the evidence that IL-17 is a key cytokine involved in various inflammatory diseases, we explored the critical role of IL-17-producing cd T cells for tumor development in tumor-bearing mouse model. IL-17 À/À mice exhibited a significant reduction of tumor growth, concomitantly with the decrease of vascular density at lesion area, indicating a pro-tumor property of IL-17. Among tumor-infiltrating lymphocytes (TIL), cd T cells were the major cellular source of IL-17. Analysis of TCR repertoires in TIL-cd T cells showed that circulating cd T cells, but not skin resident Vc5 1 cd T cells, produced IL-17. Neutralizing antibodies against IL-23, IL-6, and TGF-b, which were produced within the tumor microenvironment, inhibited the induction of IL-17-producing cd T cells. IL-17 production by tumor-infiltrating cd T cells was blocked by anti-cdTCR or anti-NKG2D antibodies, indicating that these ligands, expressed within the tumor microenvironment, are involved in cd T-cell activation. The IL-17-producing TIL-cd T cells exhibited reduced levels of perforin mRNA expression, but increased levels of COX-2 mRNA expression. Together, our findings support the novel concept that IL-17-producing cd T cells, generated in response to tumor microenvironment, act as tumor-promoting cells by inducing angiogenesis. IntroductionIn order to understand how tumor cells can escape immune surveillance mechanisms and thus develop anti-tumor therapies, it is critically important to investigate the mechanisms by which the immune system interacts with the tumor microenvironment. The tumor microenvironment, which is mainly composed of tumor cells, stromal cells, and tumor-infiltrating immune cells, is entirely different from noncancerous tissues. This unique microenvironment potently inhibits immune responses against tumor cells via various soluble mediators and contact-dependent mechanisms [1,2]. Previously, it was suggested that T-cell Eur. J. Immunol. 2010. 40: 1927-1937 DOI 10.1002 Cellular immune response 1927 responses within the local tumor tissue are completely inhibited. However, this concept was abandoned following the discovery of the regulatory T-cell and Th17 cell subsets, which are activated rather than suppressed in the tumor microenvironment via TGF-b and/or IL-6. Thus, the tumor microenvironment is conducive to IL-17 production. In fact, it has been shown that IL-17 is produced in human and murine tumor tissues [3][4][5]. Tumor cells promote neo-vascularization into tumor tissues through hyperproduction of angiogenic factors, which also support their own abnormal proliferation and survival [6]. It has been reported that tumor cells over-expressing IL-17 significantly promote new vessel growth into the tumor tissues [5]; however, physiological effects of IL-17 on tumor progression remain to be defined. Th17 differentiation from naïve CD4 1 T cells is regulated by TGF-b and IL-6. Proliferation, maintenance and full maturation of these cells are controlled by . Recently, it has been shown that IL-17 is produced by diverse T...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis

et al. 2010

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“…Mice in the first group were injected with pretreated labeled cells in a volume of 0.5 ml. Pretreatment of YS1093 cells was performed as follows: 2 ml of PKH-26-labeled YS1093 cells (1 ϫ 10 7 /ml) were treated with 40 g of anti-TCR␤ F(abЈ) 2 MAb or normal hamster IgG and, after washing, suspended in 0.5 ml of PBS. The second group was injected with 2 ϫ 10 7 YS1093 cells mixed with 600 g of anti-I-E k , anti-I-Ak or anti-I-Ad MAb in a volume of 0.5 ml.…”

Section: Discussionmentioning

confidence: 99%

“…The migration of fluorescence-labeled YS1093 cells into S1509a tumor tissue was clearly blocked by pretreatment with anti-TCR␤ F(abЈ) 2 (Fig. 7b) or by i.v.…”

Section: Migration Of Fluorescence-labeled Ys1093 Cells Into S1509a Tmentioning

confidence: 99%

“…1 After our report was published, other investigators also reported that cooperation between passively transferred specific CD4 ϩ Th cells and host CD8 ϩ T cells leads to tumor eradication in vivo. [2][3][4] These investigators also hypothesized that the transferred Th1 cells migrate into local tumor sites, where they secrete IFN-␥ and other cytokines and thereby activate antitumor CD8 ϩ CTLs in vivo. 2,3 However, the mechanisms by which the tumors in TBHs are eradicated by i.v.…”

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Role of α4 integrin and its ligand VCAM‐1 in the specific extravasation of a tumor‐specific TH2 clone into tumor tissue that initiates its rejection

Jin

Shen

Fujimoto

2004

Intl Journal of Cancer

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The effectiveness of anticancer immunotherapeutic strategies involving the transfer of tumor-specific T cells depends on appropriate lymphocyte-endothelial cell interactions that facilitate the migration of lymphocytes into tumor. Here, we investigated the molecular mechanisms underlying the migration of the antigen-specific Th2 CD4 ؉ T-cell clone YS1093 into S1509a tumor tissue. YS1093 is specific for the S1509a tumor but does not recognize the S713a tumor. Transfer of YS1093 cells into mice bearing both S1509a and S713a tumors caused only the S1509a tumor to regress. This regres-

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Transfer of IFNγ-depleted CD4+ T cells together with CD8+ T cells leads to rejection of murine kidney sarcoma in mice

2000

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In the murine kidney sarcoma, vaccination with the tumor‐specific large T antigen induces protective immunity against the tumor. Immunity is dependent both on CD8+ cytotoxic T cells and on CD4+ T‐helper cells. We analyzed whether the cytokine phenotype of induced CD4+ T‐effector cells might determine whether or not the tumor is successfully rejected. By intracytoplasmic staining of CD4+ cells, IFNγ‐producing (Th1), IL‐4–producing (Th2), and IL‐10–expressing cells could be identified in vaccinated and non‐vaccinated animals responding to tumor growth. Vaccinated mice rejecting the tumor showed an increase in the percentage of IL‐4–producing (Th2) cells. In contrast, in non‐vaccinated mice succumbing to the tumor, the immunosuppressive IL‐10–producing cells became more abundant and the frequency of IFNγ‐expressing cells dropped at later time points. Yet, dominance by either a Th1 or a Th2 response could not be observed. To further clarify the relevance of these subsets, Th1 cells were enriched by cell sorting according to IFNγ surface expression. Enriched Th1 and depleted cells, mainly consisting of the Th2 phenotype, were transferred together with CD8+ T cells. Surprisingly, immunity could be transferred either with Th1 or Th2 cells, but Th2 cells were slightly more efficient. This suggests that, at least in the effector phase, a Th1 phenotype is not crucial for the rejection. Our findings support the view that the Th1/Th2 dichotomy is not central in T‐cell–mediated tumor rejection. Int. J. Cancer 87:673–679, 2000. © 2000 Wiley‐Liss, Inc.

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Distinct Role of Antigen-Specific T Helper Type 1 (Th1) and Th2 Cells in Tumor Eradication in Vivo

Cited by 401 publications

References 43 publications

Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis

Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis

Role of α4 integrin and its ligand VCAM‐1 in the specific extravasation of a tumor‐specific TH2 clone into tumor tissue that initiates its rejection

Transfer of IFNγ-depleted CD4+ T cells together with CD8+ T cells leads to rejection of murine kidney sarcoma in mice

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