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

Cancer Immunology, Immunotherapy volume 71, pages 1331–1343 (2022)Cite this article

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.

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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

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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).

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Authors and Affiliations

  1. Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Honjo 1-1-1, Chuouku, Kumamoto, 860-8556, Japan

    Cheng Pan, Yukio Fujiwara, Hasita Horlad, Toyohisa Iriki, Daisuke Shiraishi & Yoshihiro Komohara

  2. Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto, Japan

    Yoshihiro Komohara

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  1. Cheng Pan
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  2. Yukio Fujiwara
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  3. Hasita Horlad
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Correspondence to Yukio Fujiwara or Yoshihiro Komohara.

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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

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

Keywords

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