Gene expression profile of peripheral blood mononuclear cells may contribute to the identification and immunological classification of breast cancer patients

  • Eiji SuzukiEmail author
  • Masahiro Sugimoto
  • Kosuke Kawaguchi
  • Fengling Pu
  • Ryuji Uozumi
  • Ayane Yamaguchi
  • Mariko Nishie
  • Moe Tsuda
  • Takeshi Kotake
  • Satoshi Morita
  • Masakazu Toi
Original Article



It has been reported that the gene expression profile of peripheral blood mononuclear cells (PBMCs) exhibits a unique gene expression signature in several types of cancer. In this study, we aimed to explore the breast cancer patient-specific gene expression profile of PBMCs and discuss immunological insight on host antitumor immune responses.


We comprehensively analyzed the gene expression of PBMCs by RNA sequencing in the breast cancer patients as compared to that of healthy volunteers (HVs). Pathway enrichment analysis was performed on MetaCoretm to search the molecular pathways associated with the gene expression profile of PBMCs in cancer patients compared with HVs.


We found a significant unique gene expression signature, such as the Toll-like receptor (TLR) 3- and TLR4-induced Toll/interleukin-1 receptor domain-containing adapter molecule 1 (TICAM1)-specific signaling pathway in the breast cancer patients as compared to that of healthy volunteers. Distinctive immunological gene expression profiles also showed the possibility of classifying breast cancer patients into subgroups such as T-cell inhibitory and monocyte-activating groups independent of known phenotypes of breast cancer.


These preliminary findings suggest that evaluation of gene expression patterns of PBMCs might be both a less invasive diagnostic procedure and a useful way to reveal immunological insight of breast cancer, including biomarkers for cancer immunotherapy, such as immune checkpoint inhibitor therapy.


Immuno-oncology Gene expression profile RNA sequencing Peripheral blood mononuclear cells Immune checkpoint molecule 



We thank the medical staff of the Department of Breast Surgery of Kyoto University Hospital for their help in the recruitment of patients and collection of samples. This work was supported by JSPS KAKENHI Grant Number 17K10546.

Compliance with ethical standards

Conflict of interest

All authors declare no conflicts of interests in the authorship or publication of this article.

Supplementary material

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Supplementary material 1 (PDF 39 KB)
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Supplementary material 2 (DOCX 36 KB)
12282_2018_920_MOESM3_ESM.docx (17 kb)
Supplementary material 3 (DOCX 16 KB)


  1. 1.
    Dirkx AE, Oude Egbrink MG, Wagstaff J, Griffioen AW. Monocyte/macrophage infiltration in tumors: modulators of angiogenesis. J Leukoc Biol. 2006;80:1183–96.CrossRefGoogle Scholar
  2. 2.
    Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41:49–61.CrossRefGoogle Scholar
  3. 3.
    Talmadge JE, Gabrilovich DI. History of myeloid-derived suppressor cells. Nat Rev Cancer. 2013;13:739–52.CrossRefGoogle Scholar
  4. 4.
    Baine MJ, Chakraborty S, Smith LM, Mallya K, Sasson AR, Brand RE, et al. Transcriptional profiling of peripheral blood mononuclear cells in pancreatic cancer patients identifies novel genes with potential diagnostic utility. PLoS One. 2011;6:e17014.CrossRefGoogle Scholar
  5. 5.
    Showe MK, Vachani A, Kossenkov AV, Yousef M, Nichols C, Nikonova EV, et al. Gene expression profiles in peripheral blood mononuclear cells can distinguish patients with non-small cell lung cancer from patients with nonmalignant lung disease. Cancer Res. 2009;69:9202–10.CrossRefGoogle Scholar
  6. 6.
    Saeed AI, Sharov V, White J, Li J, Liang W, Bhagabati N, et al. TM4: a free, open-source system for microarray data management and analysis. Biotechniques. 2003;34:374–8.CrossRefGoogle Scholar
  7. 7.
    Solana R, Tarazona R, Gayoso I, Lesur O, Dupuis G, Fulop T. Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans. Semin Immunol. 2012;24:331–41.CrossRefGoogle Scholar
  8. 8.
    Sasaki S, Sullivan M, Narvaez CF, Holmes TH, Furman D, Zheng NY, et al. Limited efficacy of inactivated influenza vaccine in elderly individuals is associated with decreased production of vaccine-specific antibodies. J Clin Investig. 2011;121:3109–19.CrossRefGoogle Scholar
  9. 9.
    Aspinall R, Andrew D. Thymic involution in aging. J Clin Immunol. 2000;20:250–6.CrossRefGoogle Scholar
  10. 10.
    Matsumoto M, Kikkawa S, Kohase M, Miyake K, Seya T. Establishment of a monoclonal antibody against human Toll-like receptor 3 that blocks double-stranded RNA-mediated signaling. Biochem Biophys Res Commun. 2002;293:1364–9.CrossRefGoogle Scholar
  11. 11.
    Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001;413:732–8.CrossRefGoogle Scholar
  12. 12.
    Imai Y, Kuba K, Neely GG, Yaghubian-Malhami R, Perkmann T, van Loo G, et al. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell. 2008;133:235–49.CrossRefGoogle Scholar
  13. 13.
    Brglez V, Lambeau G, Petan T. Secreted phospholipases A2 in cancer: diverse mechanisms of action. Biochimie. 2014;107 Pt A:114–23.CrossRefGoogle Scholar
  14. 14.
    Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201:233–40.CrossRefGoogle Scholar
  15. 15.
    Chen WC, Lai YH, Chen HY, Guo HR, Su IJ, Chen HH. Interleukin-17-producing cell infiltration in the breast cancer tumour microenvironment is a poor prognostic factor. Histopathology. 2013;63:225–33.CrossRefGoogle Scholar
  16. 16.
    Cochaud S, Giustiniani J, Thomas C, Laprevotte E, Garbar C, Savoye AM, et al. IL-17A is produced by breast cancer TILs and promotes chemoresistance and proliferation through ERK1/2. Sci Rep. 2013;3:3456.CrossRefGoogle Scholar
  17. 17.
    Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996;17:138–46.CrossRefGoogle Scholar
  18. 18.
    Dong Y, Sun Q, Zhang X. PD-1 and its ligands are important immune checkpoints in cancer. Oncotarget. 2017;8:2171–86.PubMedGoogle Scholar
  19. 19.
    Kaiko GE, Horvat JC, Beagley KW, Hansbro PM. Immunological decision-making: how does the immune system decide to mount a helper T-cell response? Immunology. 2008;123:326–38.CrossRefGoogle Scholar
  20. 20.
    Loke P, Allison JP. PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc Natl Acad Sci USA. 2003;100:5336–41.CrossRefGoogle Scholar
  21. 21.
    Riella LV, Paterson AM, Sharpe AH, Chandraker A. Role of the PD-1 pathway in the immune response. Am J Transplant. 2012;12:2575–87.CrossRefGoogle Scholar

Copyright information

© The Japanese Breast Cancer Society 2018

Authors and Affiliations

  • Eiji Suzuki
    • 1
    Email author
  • Masahiro Sugimoto
    • 2
  • Kosuke Kawaguchi
    • 1
  • Fengling Pu
    • 1
  • Ryuji Uozumi
    • 3
  • Ayane Yamaguchi
    • 1
  • Mariko Nishie
    • 1
  • Moe Tsuda
    • 1
  • Takeshi Kotake
    • 1
  • Satoshi Morita
    • 3
  • Masakazu Toi
    • 1
  1. 1.Breast Surgery DepartmentKyoto UniversityKyotoJapan
  2. 2.Health Promotion and Preemptive Medicine, Research and Development Center for Minimally Invasive TherapiesTokyo Medical UniversityTokyoJapan
  3. 3.Department of Biomedical Statistics and BioinformaticsKyoto UniversityKyotoJapan

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