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01-06-2021 | Kidney Cancer | Original Article

Let-7d inhibits intratumoral macrophage M2 polarization and subsequent tumor angiogenesis by targeting IL-13 and IL-10

Authors: Boxing Su, Haibo Han, Yanqing Gong, Xuesong Li, Chaoyue Ji, Jingjing Yao, Jianghui Yang, Weiguo Hu, Wei Zhao, Jianxing Li, Gang Zhang, Liqun Zhou

Published in: Cancer Immunology, Immunotherapy | Issue 6/2021

Abstract

The microRNA let-7d has been reported to be a tumor suppressor in renal cell carcinoma (RCC). Tumor-associated macrophages (TAM) are M2-polarized macrophages that can enhance tumor growth and angiogenesis in many human cancers. However, the role of let-7d in TAM-associated RCC progression remains elusive. First, we observed a strongly inverse correlation between let-7d expression and microvessel density in RCC tissues. Furthermore, the proliferation, migration, and tube formation of HUVECs were significantly inhibited by conditioned medium from a coculture system of the phorbol myristate acetate pretreated human THP-1 macrophages and let-7d-overexpressing RCC cells. Moreover, the proportion of M2 macrophages was significantly lower in the group that was cocultured with let-7d-overexpressing RCC cells. Subcutaneous xenografts formed by the injection of let-7d-overexpressing RCC cells together with THP-1 cells resulted in a significant decrease in the M2 macrophage ratio and microvessel density compared with those formed by the injection of control RCC cells with THP-1 cells. In silico and experimental analysis revealed interleukin-10 (IL-10) and IL-13 as let-7d target genes. Importantly, the addition of IL-10 and IL-13 counteracted the inhibitory effects of the conditioned medium from the coculture system with let-7d-overexpressing RCC cells in vitro. Additionally, overexpression of IL-10 and IL-13 reversed the effects of let-7d on macrophage M2 polarization and tumor angiogenesis in vivo. Finally, the expression of IL-10 and IL-13 were inversely correlated with the expression of let-7d in RCC clinical specimens. These results suggest that let-7d may inhibit intratumoral macrophage M2 polarization and subsequent tumor angiogenesis by targeting IL-10 and IL-13.

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McDermott DF, Huseni MA, Atkins MB et al (2018) Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med 24(6):749–757CrossRefPubMedPubMedCentral

Viallard C, Larrivee B (2017) Tumor angiogenesis and vascular normalization: alternative therapeutic targets. Angiogenesis 20(4):409–426CrossRefPubMed

Mantovani A, Sozzani S, Locati M et al (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23(11):549–555CrossRefPubMed

Lu G, Zhang R, Geng S et al (2015) Myeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization. Nat Commun 6:6676CrossRefPubMed

Murray PJ, Allen JE, Biswas SK et al (2014) Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41(1):14–20CrossRefPubMedPubMedCentral

Tjiu JW, Chen JS, Shun CT et al (2009) Tumor-associated macrophage-induced invasion and angiogenesis of human basal cell carcinoma cells by cyclooxygenase-2 induction. J Invest Dermatol 129(4):1016–1025CrossRefPubMed

Erreni M, Mantovani A, Allavena P (2011) Tumor-associated Macrophages (TAM) and Inflammation in Colorectal Cancer. Cancer Microenviron 4(2):141–154CrossRefPubMed

Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4(1):71–78CrossRefPubMed

Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141(1):39–51CrossRefPubMedPubMedCentral

10.

Xu L, Zhu Y, Chen L et al (2014) Prognostic value of diametrically polarized tumor-associated macrophages in renal cell carcinoma. Ann Surg Oncol 21(9):3142–3150CrossRefPubMed

11.

Su B, Zhao W, Shi B et al (2014) Let-7d suppresses growth, metastasis, and tumor macrophage infiltration in renal cell carcinoma by targeting COL3A1 and CCL7. Mol Cancer 13:206CrossRefPubMedPubMedCentral

12.

Miyake M, Hori S, Morizawa Y et al (2016) CXCL1-mediated interaction of cancer cells with tumor-associated macrophages and cancer-associated fibroblasts promotes tumor progression in human bladder cancer. Neoplasia 18(10):636–646CrossRefPubMedPubMedCentral

13.

Desai N, Ludgin J, Goldberg J et al (2013) Development of a xeno-free non-contact co-culture system for derivation and maintenance of embryonic stem cells using a novel human endometrial cell line. J Assist Reprod Genet 30(5):609–615CrossRefPubMedPubMedCentral

14.

Wang D, Stockard CR, Harkins L et al (2008) Immunohistochemistry in the evaluation of neovascularization in tumor xenografts. Biotech Histochem 83(3–4):179–189CrossRefPubMedPubMedCentral

15.

Denton AE, Roberts EW, Fearon DT (2018) Stromal cells in the tumor microenvironment. Adv Exp Med Biol 1060:99–114CrossRefPubMed

16.

Tuna B, Yorukoglu K, Unlu M et al (2006) Association of mast cells with microvessel density in renal cell carcinomas. Eur Urol 50(3):530–534CrossRefPubMed

17.

Jones J, Otu H, Spentzos D et al (2005) Gene signatures of progression and metastasis in renal cell cancer. Clin Cancer Res 11(16):5730–5739CrossRefPubMed

18.

Li W, Zhu W, Che J et al (2013) Microarray profiling of human renal cell carcinoma: identification for potential biomarkers and critical pathways. Kidney Blood Press Res 37(4–5):506–513CrossRefPubMed

19.

Chevrier S, Levine JH, Zanotelli V et al (2017) An immune atlas of clear cell renal cell carcinoma. Cell 169(4):736–749CrossRefPubMedPubMedCentral

20.

Yang Z, Xie H, He D et al (2016) Infiltrating macrophages increase RCC epithelial mesenchymal transition (EMT) and stem cell-like populations via AKT and mTOR signaling. Oncotarget 7(28):44478–44491CrossRefPubMedPubMedCentral

21.

Toge H, Inagaki T, Kojimoto Y et al (2009) Angiogenesis in renal cell carcinoma: the role of tumor-associated macrophages. Int J Urol 16(10):801–807CrossRefPubMed

22.

Fischer C, Jonckx B, Mazzone M et al (2007) Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131(3):463–475CrossRefPubMed

23.

Tan HY, Wang N, Man K et al (2015) Autophagy-induced RelB/p52 activation mediates tumour-associated macrophage repolarisation and suppression of hepatocellular carcinoma by natural compound baicalin. Cell Death Dis 6:e1942CrossRefPubMedPubMedCentral

24.

Jin H, He Y, Zhao P et al (2019) Targeting lipid metabolism to overcome EMT-associated drug resistance via integrin beta3/FAK pathway and tumor-associated macrophage repolarization using legumain-activatable delivery. Theranostics 9(1):265–278CrossRefPubMedPubMedCentral

25.

Ohba K, Miyata Y, Matsuo T et al (2014) High expression of Twist is associated with tumor aggressiveness and poor prognosis in patients with renal cell carcinoma. Int J Clin Exp Pathol 7(6):3158–3165PubMedPubMedCentral

26.

Lee JH, Lee GT, Woo SH et al (2013) BMP-6 in renal cell carcinoma promotes tumor proliferation through IL-10-dependent M2 polarization of tumor-associated macrophages. Cancer Res 73(12):3604–3614CrossRefPubMed

27.

Barros MH, Hauck F, Dreyer JH et al (2013) Macrophage polarisation: an immunohistochemical approach for identifying M1 and M2 macrophages. PLoS ONE 8(11):e80908CrossRefPubMedPubMedCentral

28.

Rakaee M, Busund LR, Jamaly S et al (2019) Prognostic value of macrophage phenotypes in resectable non-small cell lung cancer assessed by multiplex immunohistochemistry. Neoplasia 21(3):282–293CrossRefPubMedPubMedCentral

29.

Ichimura T, Morikawa T, Kawai T et al (2014) Prognostic significance of CD204-positive macrophages in upper urinary tract cancer. Ann Surg Oncol 21(6):2105–2112CrossRefPubMed

30.

Kawachi A, Yoshida H, Kitano S et al (2018) Tumor-associated CD204(+) M2 macrophages are unfavorable prognostic indicators in uterine cervical adenocarcinoma. Cancer Sci 109(3):863–870CrossRefPubMedPubMedCentral

31.

Wittke F, Hoffmann R, Buer J et al (1999) Interleukin 10 (IL-10): an immunosuppressive factor and independent predictor in patients with metastatic renal cell carcinoma. Br J Cancer 79(7–8):1182–1184CrossRefPubMedPubMedCentral

32.

Daurkin I, Eruslanov E, Stoffs T et al (2011) Tumor-associated macrophages mediate immunosuppression in the renal cancer microenvironment by activating the 15-lipoxygenase-2 pathway. Cancer Res 71(20):6400–6409CrossRefPubMed

33.

Roszer T (2015) Understanding the mysterious M2 macrophage through activation markers and effector mechanisms. Mediators Inflamm 2015:816460CrossRefPubMedPubMedCentral

34.

Hallett MA, Venmar KT, Fingleton B et al (2012) Cytokine stimulation of epithelial cancer cells: the similar and divergent functions of IL-4 and IL-13. Cancer Res 72(24):6338–6343CrossRefPubMedPubMedCentral

35.

Terabe M, Matsui S, Noben-Trauth N et al (2000) NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nat Immunol 1(6):515–520CrossRefPubMed

36.

Gabitass RF, Annels NE, Stocken DD et al (2011) Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13. Cancer Immunol Immunother 60(10):1419–1430CrossRefPubMedPubMedCentral

37.

Chang Y, Xu L, An H et al (2015) Expression of IL-4 and IL-13 predicts recurrence and survival in localized clear-cell renal cell carcinoma. Int J Clin Exp Pathol 8(2):1594–1603PubMedPubMedCentral

38.

Satoh T, Takeuchi O, Vandenbon A et al (2010) The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol 11(10):936–944CrossRefPubMed

39.

Gao S, Zhou J, Liu N et al (2015) Curcumin induces M2 macrophage polarization by secretion IL-4 and/or IL-13. J Mol Cell Cardiol 85:131–139CrossRefPubMed

Title: Let-7d inhibits intratumoral macrophage M2 polarization and subsequent tumor angiogenesis by targeting IL-13 and IL-10
Authors: Boxing Su
Haibo Han
Yanqing Gong
Xuesong Li
Chaoyue Ji
Jingjing Yao
Jianghui Yang
Weiguo Hu
Wei Zhao
Jianxing Li
Gang Zhang
Liqun Zhou
Publication date: 01-06-2021
Publisher: Springer Berlin Heidelberg
Keywords: Kidney Cancer
Kidney Cancer
Kidney Cancer
Published in: Cancer Immunology, Immunotherapy / Issue 6/2021
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-020-02791-6

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