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Histone deacetylase 6 regulates the immunosuppressive properties of cancer-associated fibroblasts in breast cancer through the STAT3–COX2-dependent pathway

Oncogene volume 37, pages 5952–5966 (2018)Cite this article

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Abstract

Cancer-associated fibroblasts (CAFs) are important components in breast tumors and essential for tumor progression and metastasis. However, the role of epigenetic modification in driving the function of CAFs within breast tumors is only marginally known. Herein, we reported that histone deacetylase 6 (HDAC6), one of class II histone deacetylases, was frequently upregulated in the CAFs of breast tumor and promotes an immunosuppressive microenvironment. The genetic or pharmacologic disruption of HDAC6 in CAFs delays tumor growth, inhibits the tumor recruitment of myeloid-derived suppressor cells and regulatory T cells, alters the macrophage phenotype switch, and increases the CD8+ and CD4+ T-cell activation in vivo. Mechanistically, we identified prostaglandin E2/cyclooxygenase-2 (COX2) as a major target of HDAC6 in CAFs by regulating STAT3 activation. Overexpressing COX2 in HDAC6-knockdown CAFs can completely restore the immunosuppressive properties of the fibroblasts. Clinically, a positive correlation among the stromal expression levels of HDAC6, p-STAT3, and COX2 in human breast cancer was observed. High-stromal expression of HDAC6 was markedly associated with poor survival outcome. Overall, our findings indicated that fibroblastic HDAC6 was a vital epigenetic mediator involved in programming an immunosuppressive tumor microenvironment that dampens antitumor immunity. Thus, HDAC6 may be a good potential target to improve breast cancer immunotherapy.

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References

  1. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. NatMed. 2013;19:1423–37.

    CAS  Google Scholar 

  2. Sharon Y, Raz Y, Cohen N, Ben-Shmuel A, Schwartz H, Geiger T, et al. Tumor derived osteopontin reprograms normal mammary fibroblasts to promote inflammation and tumor growth in breast cancer. Cancer Res. 2015;75:963–73.

    Article  CAS  Google Scholar 

  3. Kalluri R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer . 2003;3:422–33.

    Article  CAS  Google Scholar 

  4. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7.

    Article  CAS  Google Scholar 

  5. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6:392–401.

    Article  CAS  Google Scholar 

  6. Feig C, Jones J, Kraman M, Wells R, Deonarine A, Chan D, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci USA. 2013;110:20212–7.

    Article  CAS  Google Scholar 

  7. Ozdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014;25:719–34.

    Article  CAS  Google Scholar 

  8. Loeffler M, Kruger JA, Niethammer AG, Reisfeld RA. Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Invest. 2006;116:1955–62.

    Article  CAS  Google Scholar 

  9. Nakasone ES, Askautrud HA, Kees T, Park JH, Plaks V, Ewald AJ, et al. Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell. 2012;21:488–503.

    Article  CAS  Google Scholar 

  10. Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21:418–29.

    Article  CAS  Google Scholar 

  11. Shalapour S, Font-Burgada J, Di Caro G, Zhong Z, Sanchez-Lopez E, Dhar D, et al. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature. 2015;521:94–98.

    Article  CAS  Google Scholar 

  12. Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N, Frese KK, et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut. 2013;62:112–20.

    Article  CAS  Google Scholar 

  13. Scherz-Shouval R, Santagata S, Mendillo ML, Sholl LM, Ben-Aharon I, Beck AH, et al. The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy. Cell. 2014;158:564–78.

    Article  CAS  Google Scholar 

  14. Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16:582–98.

    Article  CAS  Google Scholar 

  15. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, et al. Lysine acetylation targets protein complexes andcoregulatesmajor cellular functions. Science. 2009;325:834–40.

    Article  CAS  Google Scholar 

  16. Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 2006;6:38–51.

    Article  CAS  Google Scholar 

  17. Frangogiannis NG. The extracellular matrix in myocardial injury, repair, and remodeling. J Clin Invest. 2017;127:1600–12.

    Article  Google Scholar 

  18. Marsh T, Pietras K, McAllister SS. Fibroblasts as architects of cancer pathogenesis. Biochim Biophys Acta. 2013;1832:1070–8.

    Article  CAS  Google Scholar 

  19. Schuetze KB, McKinsey TA, Long CS. Targeting cardiac fibroblasts to treat fibrosis of the heart: focus on HDACs. J Mol Cell Cardiol. 2014;70:100–7.

    Article  CAS  Google Scholar 

  20. Zheng H, Zhao W, Yan C, Watson CC, Massengill M, Xie M, et al. HDAC inhibitors enhance T-cell chemokine expression and augment response to PD-1 immunotherapy in lung adenocarcinoma. Clin Cancer Res. 2016;22:4119–32.

    Article  CAS  Google Scholar 

  21. Guerriero JL, SotayoA, Ponichtera HE, Castrillon JA, Pourzia AL, Schad S, et al. Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature. 2017;543:428–32.

    Article  CAS  Google Scholar 

  22. Lyssiotis CA, Kimmelman AC. Metabolic interactions in the tumor microenvironment. Trends Cell Biol. 2017;27:863–75.

    Article  CAS  Google Scholar 

  23. Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, et al. HDAC6 is a microtubule-associated deacetylase. Nature. 2002;417:455–8.

    Article  CAS  Google Scholar 

  24. Lee HJ, Diaz MF, Ewere A, Olson SD, Cox CS Jr, Wenzel PL. Focal adhesion kinase signaling regulates anti-inflammatory function of bone marrow mesenchymal stromal cells induced by biomechanical force. Cell Signal. 2017;38:1–9.

    Article  Google Scholar 

  25. Wang S, Liu Z, Wang L, Zhang X. NF-kappaB signaling pathway, inflammation and colorectal cancer. Cell Mol Immunol. 2009;6:327–34.

    Article  CAS  Google Scholar 

  26. Williams L, Bradley L, Smith A, Foxwell B. Signal transducer and activator of transcription 3 is the dominant mediator of the anti-inflammatory effects of IL-10 in human macrophages. J Immunol. 2004;172:567–76.

    Article  CAS  Google Scholar 

  27. Smith MP, Wellbrock C. Molecular pathways: maintaining MAPK inhibitor sensitivity by targeting nonmutational tolerance. Clin Cancer Res. 2016;22:5966–70.

    Article  CAS  Google Scholar 

  28. Cheng F, Lienlaf M, Wang HW, Perez-Villarroel P, Lee C, Woan K, et al. A novel role for histone deacetylase 6 in the regulation of the tolerogenic STAT3/IL-10 pathway in APCs. J Immunol. 2014;193:2850–62.

    Article  CAS  Google Scholar 

  29. Palijan A, Fernandes I, Bastien Y, Tang L, Verway M, Kourelis M, et al. Function of histone deacetylase 6 as a cofactor of nuclear receptor coregulator LCoR. J BiolChem. 2009;284:30264–74.

    CAS  Google Scholar 

  30. Terranova-Barberio M, Thomas S, Munster PN. Epigenetic modifiers in immunotherapy: a focus on checkpoint inhibitors. Immunotherapy. 2016;8:705–19.

    Article  CAS  Google Scholar 

  31. Schoepp M, Ströse AJ, Haier J, Dysregulation of miRNA expression in cancer associated fibroblasts (CAFs) and its consequences on the tumor microenvironment. Cancers. 2017;9:54

    Article  Google Scholar 

  32. Cohen N, Shani O, Raz Y, Sharon Y, Hoffman D, Abramovitz L, et al. Fibroblasts drive an immuno-suppressive and growth-promoting microenvironment in breast cancer via secretion of Chitinase 3-like 1. Oncogene. 2017;36:4457–68.

    Article  CAS  Google Scholar 

  33. Li L, Fang R, Liu B, Shi H, Wang Y, Zhang W, et al. Deacetylation of tumor-suppressor MST1 in Hippo pathway induces its degradation through HBXIP-elevated HDAC6 in promotion of breast cancer growth. Oncogene. 2016;35:4048–57.

    Article  CAS  Google Scholar 

  34. Putcha P, Yu J, Rodriguez-Barrueco R, Saucedo-Cuevas L, Villagrasa P, Murga-Penas E, et al. HDAC6 activity is a non-oncogene addiction hub for inflammatory breast cancers. Breast Cancer Res. 2015;17:149.

    Article  Google Scholar 

  35. Soo Youn G, JuSM, Choi SY, Park J. HDAC6 mediates HIV-1 tat-induced proinflammatory responses by regulating MAPK-NF-kappaB/AP-1pathways in astrocytes. Glia. 2015;63:1953–65.

    Article  Google Scholar 

  36. Cheng F, Lienlaf M, Perez-Villarroel P, Wang HW, Lee C, Woan K, et al. Divergent roles of histone deacetylase 6 (HDAC6) and histone deacetylase 11 (HDAC11) on the transcriptional regulation of IL10 in antigen presenting cells. Mol Immunol. 2014;60:44–53.

    Article  CAS  Google Scholar 

  37. Kumar V, Patel S, Tcyganov E, Gabrilovich DI. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 2016;37:208–20.

    Article  CAS  Google Scholar 

  38. Sharma S, Yang SC, Zhu L, Reckamp K, Gardner B, Baratelli F, et al. Tumor cyclooxygenase-2/prostaglandinE2-dependent promotion of FOXP3 expression and CD4 + CD25 + T regulatory cell activities in lung cancer. Cancer Res. 2005;65:5211–20.

    Article  CAS  Google Scholar 

  39. Kim K, Skora AD, Li Z, Liu Q, Tam AJ, Blosser RL, et al. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci USA. 2014;111:11774–9.

    Article  CAS  Google Scholar 

  40. Wang H, Franco F, Ho PC. Metabolic regulation of Tregs in cancer: opportunities for immunotherapy. Trends Cancer. 2017;3:583–92.

    Article  Google Scholar 

  41. Karavitis J, Zhang M. COX2 regulation of breast cancer bone metastasis. Oncoimmunology. 2013;2:e23129.

    Article  Google Scholar 

  42. Chang AL, Miska J, Wainwright DA, Dey M, Rivetta CV, Yu D, et al. CCL2 produced by the glioma microenvironment is essential for the recruitment of regulatory T cells and myeloid-derived suppressor cells. Cancer Res. 2016;76:5671–82.

    Article  CAS  Google Scholar 

  43. Yang X, Lin Y, Shi Y, Li B, Liu W, Yin W, et al. FAP promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3- CCL2 Signaling. Cancer Res. 2016;76:4124–35.

    Article  CAS  Google Scholar 

  44. Su CW, Zhang Y, Zhu YT. Stromal COX-2 signaling are correlated with colorectal cancer: a review. Crit Rev Oncol Hematol. 2016;107:33–38.

    Article  Google Scholar 

  45. Reader J, Holt D, Fulton A. Prostaglandin E2 EP receptors as therapeutic targets in breast cancer. Cancer Metastas Rev. 2011;30:449–63.

    Article  CAS  Google Scholar 

  46. Fulton AM, Ma X, Kundu N. Targeting prostaglandin E EP receptors to inhibit metastasis. Cancer Res. 2006;66:9794–7.

    Article  CAS  Google Scholar 

  47. Regulski M, Regulska K, Prukała W, Piotrowska H, Stanisz B, Murias M. COX-2 inhibitors: a novel strategy in the management of breast cancer. Drug Discov Today. 2016;21:598–615.

    Article  CAS  Google Scholar 

  48. Fanelli A, Ghisi D, Aprile PL, Lapi F. Cardiovascular and cerebrovascular risk with nonsteroidal anti-inflammatory drugs andcyclooxygenase 2 inhibitors: latest evidence and clinical implications. Ther Adv Drug Saf. 2017;8:173–82.

    Article  CAS  Google Scholar 

  49. Yan H, Zhu S, Song C, Liu N, Kang J. Bone morphogenetic protein (BMP) signaling regulates mitotic checkpoint protein levels in human breast cancer cells. Cell Signal. 2012;24:961–8.

    Article  CAS  Google Scholar 

  50. Schwartz H, Blacher E, Amer M, Livneh N, Abramovitz L, Klein A, et al. Incipient melanoma brain metastases instigate astrogliosis and neuroinflammation. Cancer Res. 2016;76:4359–71.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants obtained from the Ministry of Science and Technology of China (grant #2016YFA0101300), Science and Technology Commission of Shanghai Municipality (grant #16PJ1410200), and the Fundamental Research Funds for the Central Universities (grant #1501219171, 22120170068).

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  1. Clinical and Translational Research Center of Shanghai First Maternity & Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, No. 1239 Siping Road, Shanghai, 200092, China

    Ang Li, Ping Chen, Ye Leng & Jiuhong Kang

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Correspondence to Jiuhong Kang.

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Li, A., Chen, P., Leng, Y. et al. Histone deacetylase 6 regulates the immunosuppressive properties of cancer-associated fibroblasts in breast cancer through the STAT3–COX2-dependent pathway. Oncogene 37, 5952–5966 (2018). https://doi.org/10.1038/s41388-018-0379-9

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