Skip to main content

Cyclic sulfur compounds targeting macrophage polarization into M2/protumor phenotype and their anti-tumor effects

Abstract

Tumor-associated macrophages (TAMs), especially the M2-like phenotype, promote tumor progression, making them candidate targets for anti-tumor therapy. We previously discovered a cyclic sulfur compound, Onionin A (ONA), which suppresses tumor progression by inhibiting the M2-polarization of TAMs. In the present study, we sought to find new candidate compounds possessing a stronger effect compared to ONA by exploring compounds with structures similar to those of ONA among several cyclic sulfur compounds. A total of 81 cyclic sulfur compounds were screened, and their effects on macrophage polarization toward an M2-like phenotype were tested using human monocyte-derived macrophages (HMDMs). The anti-tumor effects of the identified candidate compounds were examined in a tumor-bearing mouse model. Three candidate compounds inhibited both IL-10- and tumor culture supernatant (TCS)-induced M2-polarization of HMDMs. These compounds also suppressed STAT3 activation in HMDMs stimulated by IL-10 and TCS, whereas these compounds had no effect on STAT3 activation in tumor cells. Furthermore, these compounds inhibited tumor cell proliferation under co-culture conditions with HMDMs, indicating that the three candidate compounds suppress tumor proliferation by regulating cell–cell interactions between tumor cells and macrophages. In addition, two of these candidate compounds had inhibitory effects on tumor growth and lung metastasis in the LM8 tumor-bearing mouse model. Our study identified new candidate cyclic sulfur compounds for anti-tumor therapy targeting the M2-polarization of TAMs.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Abbreviations

BrdU:

5-Bromo-2’-deoxyuridine

ELISA:

Enzyme-linked immunosorbent assay

FBS:

Fetal bovine serum

HMDMs:

Human monocyte-derived macrophages

ONA:

Onionin A

PBMCs:

Peripheral blood mononuclear cells

PFA:

Paraformaldehyde

rhIL-10:

Recombinant human interleukin-10

RT-qPCR:

Real-time quantitative PCR

TAMs:

Tumor-associated macrophages

TCS:

Tumor culture supernatant

TME:

Tumor microenvironment

References

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

    CAS  Article  Google Scholar 

  2. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686

    CAS  Article  Google Scholar 

  3. Komohara Y, Jinushi M, Takeya M (2014) Clinical significance of macrophage heterogeneity in human malignant tumors. Cancer Sci 105:1–8

    CAS  Article  Google Scholar 

  4. Takeya M, Komohara Y (2016) Role of tumor-associated macrophages in human malignancies: friend or foe?: TAMs in human malignancies. Pathol Int 66:491–505

    Article  Google Scholar 

  5. Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P (2017) Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 14:399–416

    CAS  Article  Google Scholar 

  6. Sica A, Bronte V (2007) Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest 117:1155–1166

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  8. Qian B-Z, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51

    CAS  Article  Google Scholar 

  9. Komohara Y, Ohnishi K, Kuratsu J, Takeya M (2008) Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol 216:15–24

    CAS  Article  Google Scholar 

  10. Clear AJ, Lee AM, Calaminici M, Ramsay AG, Morris KJ, Hallam S et al (2010) Increased angiogenic sprouting in poor prognosis FL is associated with elevated numbers of CD163+ macrophages within the immediate sprouting microenvironment. Blood 115:5053–5056

    CAS  Article  Google Scholar 

  11. Komohara Y, Hasita H, Ohnishi K, Fujiwara Y, Suzu S, Eto M et al (2011) Macrophage infiltration and its prognostic relevance in clear cell renal cell carcinoma. Cancer Sci 102:1424–1431

    CAS  Article  Google Scholar 

  12. Kurahara H, Shinchi H, Mataki Y, Maemura K, Noma H, Kubo F et al (2011) Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J Surg Res 167:e211–e219

    Article  Google Scholar 

  13. Shiraishi D, Fujiwara Y, Horlad H, Saito Y, Iriki T, Tsuboki J et al (2018) CD163 is required for protumoral activation of macrophages in human and murine sarcoma. Cancer Res 78:3255–3266

    CAS  Article  Google Scholar 

  14. Etzerodt A, Tsalkitzi K, Maniecki M, Damsky W, Delfini M, Baudoin E et al (2019) Specific targeting of CD163+ TAMs mobilizes inflammatory monocytes and promotes T cell–mediated tumor regression. J Exp Med 216:2394–2411

    CAS  Article  Google Scholar 

  15. El-Aasr M, Fujiwara Y, Takeya M, Ikeda T, Tsukamoto S, Ono M et al (2010) Onionin A from Allium cepa inhibits macrophage activation. J Nat Prod 73:1306–1308

    CAS  Article  Google Scholar 

  16. Tsuboki J, Fujiwara Y, Horlad H, Shiraishi D, Nohara T, Tayama S et al (2016) Onionin A inhibits ovarian cancer progression by suppressing cancer cell proliferation and the protumour function of macrophages. Sci Rep 6:29588

    CAS  Article  Google Scholar 

  17. Fujiwara Y, Horlad H, Shiraishi D, Tsuboki J, Kudo R, Ikeda T et al (2016) Onionin A, a sulfur-containing compound isolated from onions, impairs tumor development and lung metastasis by inhibiting the protumoral and immunosuppressive functions of myeloid cells. Mol Nutr Food Res 60:2467–2480

    CAS  Article  Google Scholar 

  18. Asai T, Ueda T, Itoh K, Yoshioka K, Aoki Y, Mori S et al (1998) Establishment and characterization of a murine osteosarcoma cell line (LM8) with high metastatic potential to the lung. Int J Cancer 76:418–422

    CAS  Article  Google Scholar 

  19. Komohara Y, Hirahara J, Horikawa T, Kawamura K, Kiyota E, Sakashita N et al (2006) AM-3K, an anti-macrophage antibody, recognizes CD163, a molecule associated with an anti-inflammatory macrophage phenotype. J Histochem Cytochem 54:763–771

    CAS  Article  Google Scholar 

  20. Horlad H, Fujiwara Y, Takemura K, Ohnishi K, Ikeda T, Tsukamoto H et al (2013) Corosolic acid impairs tumor development and lung metastasis by inhibiting the immunosuppressive activity of myeloid-derived suppressor cells. Mol Nutr Food Res 57:1046–1054

    CAS  Article  Google Scholar 

  21. Fujiwara Y, Komohara Y, Ikeda T, Takeya M (2011) Corosolic acid inhibits glioblastoma cell proliferation by suppressing the activation of signal transducer and activator of transcription-3 and nuclear factor-kappa B in tumor cells and tumor-associated macrophages. Cancer Sci 102:206–211

    CAS  Article  Google Scholar 

  22. Hutchins AP, Diez D, Miranda-Saavedra D (2013) The IL-10/STAT3-mediated anti-inflammatory response: recent developments and future challenges. Brief Funct Genomics 12:489–498

    CAS  Article  Google Scholar 

  23. Yu H, Kortylewski M, Pardoll D (2007) Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment: Tumour immunology. Nat Rev Immunol 7:41–51

    CAS  Article  Google Scholar 

  24. Takaishi K, Komohara Y, Tashiro H, Ohtake H, Nakagawa T, Katabuchi H et al (2010) Involvement of M2-polarized macrophages in the ascites from advanced epithelial ovarian carcinoma in tumor progression via Stat3 activation. Cancer Sci 101:2128–2136

    CAS  Article  Google Scholar 

  25. Iriki T, Ohnishi K, Fujiwara Y, Horlad H, Saito Y, Pan C et al (2017) The cell-cell interaction between tumor-associated macrophages and small cell lung cancer cells is involved in tumor progression via STAT3 activation. Lung Cancer 106:22–32

    Article  Google Scholar 

  26. Khan MW, Saadalla A, Ewida AH, Al-Katranji K, Al-Saoudi G, Giaccone ZT et al (2018) The STAT3 inhibitor pyrimethamine displays anti-cancer and immune stimulatory effects in murine models of breast cancer. Cancer Immunol Immunother 67:13–23

    CAS  Article  Google Scholar 

  27. Komohara Y, Fujiwara Y, Ohnishi K, Takeya M (2016) Tumor-associated macrophages: potential therapeutic targets for anti-cancer therapy. Adv Drug Deliv Rev 99:180–185

    CAS  Article  Google Scholar 

  28. Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF et al (2013) CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 19:1264–1272

    CAS  Article  Google Scholar 

  29. Cannarile MA, Weisser M, Jacob W, Jegg A-M, Ries CH, Rüttinger D (2017) Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J Immunother Cancer 5:53

    Article  Google Scholar 

  30. Loberg RD, Ying C, Craig M, Day LL, Sargent E, Neeley C et al (2007) Targeting CCL2 with systemic delivery of neutralizing antibodies induces prostate cancer tumor regression in vivo. Cancer Res 67:9417–9424

    CAS  Article  Google Scholar 

  31. Beule ND, Veirman KD, Maes K, Bruyne ED, Menu E, Breckpot K et al (2017) Tumour-associated macrophage-mediated survival of myeloma cells through STAT3 activation. J Pathol 241:534–546

    Article  Google Scholar 

  32. Binnemars-Postma K, Bansal R, Storm G, Prakash J (2018) Targeting the Stat6 pathway in tumor-associated macrophages reduces tumor growth and metastatic niche formation in breast cancer. FASEB J 32:969–978

    CAS  Article  Google Scholar 

  33. Goerdt S, Orfanos CE (1999) Other functions, other genes: alternative activation of antigen-presenting cells. Immunity 10:137–142

    CAS  Article  Google Scholar 

  34. Fujiwara Y, Hizukuri Y, Yamashiro K, Makita N, Ohinishi K, Takeya M, Komohara Y, Hayashi Y (2016) Guanylate-binding protein 5 is a marker of interferon-g-induced classically activated macrophages. Clin Transl Immunol 5:e111

    Article  Google Scholar 

Download references

Acknowledgements

We thank Natsuki Abe (Nissan Chemical Industries Ltd.), Takumi Mikashima (Nissan Chemical Industries Ltd), Taito Nishino (Nissan Chemical Industries Ltd), Ms. Takana Motoyoshi (K. I. Stainer, Inc.), and Mr. Takenobu Nakagawa (Kumamoto University) for their technical assistance. This work was supported by JSPS KAKENHI (Grant Numbers 16H05162, 16K09247, 19K09555, and 19K08603).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Yukio Fujiwara or Yoshihiro Komohara.

Ethics declarations

Conflict of interest

None of the authors have any conflicts of interest in association with this study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Pan, C., Fujiwara, Y., Horlad, H. et al. Cyclic sulfur compounds targeting macrophage polarization into M2/protumor phenotype and their anti-tumor effects. Cancer Immunol Immunother 71, 1331–1343 (2022). https://doi.org/10.1007/s00262-021-03085-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-021-03085-1

Keywords

  • Tumor-associated macrophages
  • Cyclic sulfur compounds
  • Tumors
  • STAT3
  • M2-polarization