Transforming Growth Factor Subverts the Immune System into Directly Promoting Tumor Growth through Interleukin-17

Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Korea.
Cancer Research (Impact Factor: 9.33). 06/2008; 68(10):3915-23. DOI: 10.1158/0008-5472.CAN-08-0206
Source: PubMed


Overexpression of the immunosuppressive cytokine transforming growth factor beta (TGF-beta) is one strategy that tumors have developed to evade effective immunesurveillance. Using transplantable models of breast and colon cancer, we made the unexpected finding that CD8+ cells in tumor-bearing animals can directly promote tumorigenesis, by a mechanism that is dependent on TGF-beta. We showed that CD8+ splenocytes from tumor-bearing mice expressed elevated interleukin (IL)-17 when compared with naive mice, and that CD8+ T cells could be induced to make IL-17 on addition of TGF-beta and IL-6 in vitro. Treatment of mice with anti-TGF-beta antibodies in vivo reduced IL-17 expression both in the tumor and the locoregional lymph nodes. Although IL-17 has not previously been shown to act as a survival factor for epithelial cells, we found that IL-17 suppressed apoptosis of several tumor cell lines in vitro, suggesting that this altered T-cell polarization has the potential to promote tumorigenesis directly, rather than indirectly through inflammatory sequelae. Consistent with this hypothesis, knockdown of the IL-17 receptor in 4T1 mouse mammary cancer cells enhanced apoptosis and decreased tumor growth in vivo. Thus, in addition to suppressing immune surveillance, tumor-induced TGF-beta may actively subvert the CD8+ arm of the immune system into directly promoting tumor growth by an IL-17-dependent mechanism.

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    • "* P = .0096. producing Th17 and IL-17–producing CD8 + T (Tc17) cells were induced from naive CD4 + and CD8 + T cells in the presence of TGF-β and IL-6, which are highly produced in the tumor microenvironment [46] [47]. In our result, it is possible to consider that IL-17–producing cells such as Tc17 cells induced by Th1 cytokines secreted by surrounding cancer tissues produce IL-17. "
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    ABSTRACT: Several cytokines secreted from breast cancer tissues are suggested to be related to disease prognosis. We examined Th1/Th2/Th17 cytokines produced from three-dimensionally cultured breast cancer tissues and related them with patient clinical profiles. 21 tumor tissues and 9 normal tissues surgically resected from breast cancer patients were cultured in thermoreversible gelatin polymer-containing medium. Tissue growth and Th1/Th2/Th17 cytokine concentrations in the culture medium were analyzed and were related with hormone receptor expressions and patient clinical profiles. IL-6 and IL-10 were expressed highly in culture medium of both cancer and normal tissues. However, IFN-γ, TNF-α, IL-2, and IL-17A were not detected in the supernatant of the three-dimensionally cultured normal mammary gland and are seemed to be specific to breast cancer tissues. The growth abilities of hormone receptor-negative cancer tissues were significantly higher than those of receptor-positive tissues (P=0.0383). Cancer tissues of stage ≥IIB patients expressed significantly higher TNF-α levels as compared with those of patients with stage <IIB (P=0.0096). The tumor tissues resected from breast cancer patients can grow in the three-dimensional thermoreversible gelatin polymer culture system and produce Th1/Th2/Th17 cytokines. Hormone receptor-positive cancer tissues showed less growth ability. TNF-α is suggested to be a biomarker for the cancer stage. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Translational oncology
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    • "On the other hand, TGFβ suppresses both innate and adaptive immune responses in the tumor microenvironment. CTL-mediated tumor elimination is thus reduced by the presence of TGFβ [32,33]. As both 3M-052 and CpG ODN tend to reduce the level of immune suppression in the tumor microenvironment, their effect on CTLA-4 and TGFβ expression was examined. "
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    ABSTRACT: Background The TLR7/8 agonist 3M-052 and the TLR9 agonist CpG ODN both trigger innate immune responses that support the induction of tumor-specific immunity. Previous studies showed that these agonists used individually could improve the survival of mice challenged with small tumors but were of limited therapeutic benefit against large/advanced tumors. Methods Normal mice were challenged with syngeneic tumors. Once these tumors reached clinically detectable size (500–800 mm3) they were treated by intra-tumoral injection with 3M-052 and/or CpG ODN. Anti-tumor immunity and tumor growth were evaluated. Results The co-delivery of agonists targeting TLRs 7, 8 and 9 increased the number and tumoricidal activity of tumor infiltrating CTL and NK cells while reducing the frequency of immunosuppressive MDSC. The combination of 3M-052 plus CpG ODN (but not each agent alone) eradicated large primary tumors and established long-term protective immunity. Conclusion The combination of agonists targeting TLRs 7/8 and 9 represents a significant improvement in cancer immunotherapy.
    Full-text · Article · May 2014
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    • "Indeed in our previous publications, we have shown that BC-associated metastasis is significantly augmented in mice with arthritis and that IL-17A, IL-6, COX-2, VEGF, MMP-9, IGF-II, M-CSF and TNF-α are all major players [6,7]. These cytokines not only play an imperative role in arthritis but also cancer development and progression [37-48]. "
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    ABSTRACT: IL-17A is a pro-inflammatory cytokine that is normally associated with autoimmune arthritis and other pro-inflammatory conditions. Recently, IL-17A has emerged as a critical factor in enhancing breast cancer (BC)-associated metastases. We generated immune competent arthritic mouse models that develop spontaneous BC-associated bone and lung metastasis. Using these models, we have previously shown that neutralization of IL-17A resulted in significant reduction in metastasis. However, the underlying mechanism/s remains unknown. We have utilized two previously published mouse models for this study: 1) the pro-arthritic mouse model (designated SKG) injected with metastatic BC cell line (4T1) in the mammary fat pad, and 2) the PyV MT mice that develop spontaneous mammary gland tumors injected with type II collagen to induce autoimmune arthritis. Mice were treated with anti-IL-17A neutralizing antibody and monitored for metastasis and assessed for pro-inflammatory cytokines and chemokines associated with BC-associated metastasis. We first corroborate our previous finding that in vivo neutralization of IL-17A significantly reduced metastasis to the bones and lungs in both models. Next, we report that treatment with anti-IL17A antibody significantly reduced the expression of a key chemokine, CXCL12 (also known as stromal derived factor-1 (SDF - 1)) in the bones and lungs of treated mice. CXCL12 is a ligand for CXCR4 (expressed on BC cells) and their interaction is known to be critical for metastasis. Interestingly, levels of CXCR4 in the tumor remained unchanged with treatment. Consequently, protein lysates derived from the bones and lungs of treated mice were significantly less chemotactic for the BC cells than lysates from untreated mice; and addition of exogenous SDF-1 to the lysates from treated mice completely restored BC cell migration. In addition, cytokines such as IL-6 and M-CSF were significantly reduced in the lung and bone lysates following treatment. The data presented suggests that systemic neutralization of IL-17A can block the CXCR4/SDF-1 signaling pathway by reducing the expression of SDF-1 in the metastatic niches and significantly reducing metastasis in both mouse models. In our model, neutralization of IL-17A regulates SDF-1 expression in the metastatic niches either directly or indirectly via reducing levels of IL-6 and M-CSF.
    Full-text · Article · Mar 2014 · BMC Cancer
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