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A potential role for peripheral natural killer cell activity induced by preoperative chemotherapy in breast cancer patients

  • Ryungsa KimEmail author
  • Ami Kawai
  • Megumi Wakisaka
  • Yuri Funaoka
  • Naomi Yasuda
  • Masayuki Hidaka
  • Yukitaka Morita
  • Shoichro Ohtani
  • Mitsuya Ito
  • Koji Arihiro
Original Article

Abstract

Tumor-infiltrating lymphocytes are an important prognostic factor after neoadjuvant chemotherapy (NAC) in patients with breast cancer. Natural killer (NK) cells play critical roles in antitumor immune surveillance. Here, we assessed the relationship between peripheral natural killer (pNK) cell activity, tumor microenvironmental factors (TMEFs), and the therapeutic efficacy of preoperative chemotherapy in patients with breast cancer. In a cohort of 39 patients diagnosed with stage II–IV breast cancer who received NAC, we measured pNK cell activity by chromium release assay and assessed TMEF levels by next-generation sequencing. Following NAC, pNK cell activity was increased in 24/39 patients but decreased in 15/39 patients. Increased pNK cell activity following preoperative chemotherapy was associated significantly with the disappearance of axillary lymph node metastasis (Ax+; p = 0.0235). Increased pNK cell activity remained significantly associated with the disappearance of Ax+ in multivariate logistic regression analysis (OR 5.41, 95% CI 1.19–24.52, p = 0.0283). A Grade 2 or higher effect of NAC was associated with high pre-NAC cytotoxic T lymphocyte-associated protein 4 (CTLA-4) levels (p = 0.0281) and elevated post-NAC NK (p = 0.0005) cells and transforming growth factor-beta (TGF-β; p = 0.0350) levels. The disappearance of Ax+ was associated with high pre-NAC CTLA-4 levels (p = 0.0278) and elevated CD4 levels after NAC (p = 0.0250). The systemic activation of pNK cells after NAC may improve metastatic tumor elimination in patients with breast cancer owing to a release from local immunosuppression, and immune activation in the tumor microenvironment.

Keywords

Breast cancer Preoperative chemotherapy Immune response Peripheral natural killer cell (pNK) activity Transforming growth factor β Tumor microenvironment 

Abbreviations

Ax+

Axillary lymph node metastasis

CI

Confidence interval

CTLA-4

Cytotoxic T lymphocyte-associated protein 4

DTX

Docetaxel

FEC

5-Fluorouracil/epirubicin/cyclophosphamide

FFPE

Formalin-fixed paraffin embedded

HER-2

Human epidermal growth factor receptor-2

Nab-PTX

Nanoparticle albumin-bound-paclitaxel

NAC

Neoadjuvant chemotherapy

OR

Odds ratio

pNK

Peripheral natural killer

TMEF

Tumor microenvironmental factor

TN

Triple negative

Tz

Trastuzumab

Notes

Acknowledgements

The authors thank the patients and their families for their participation in the study. The authors also thank SRL. Inc. (Tokyo, Japan) for the measurement of pNK cell activity.

Author contributions

Conception and design: RK. Collection and assembly of data: RK, AK, MW, YF, NY, MH, YM, SO, MI, KA. Data analysis and interpretation: RK, AK, MH, YM. Manuscript writing: RK, YM. Final approval of manuscript: all authors.

Funding

No specific funding was received for this study.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

This study was approved by the research ethics committee of the Hiroshima Mark Clinic on July 1, 2012. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Breast SurgeryHiroshima Mark ClinicHiroshimaJapan
  2. 2.Genetic Testing Gene ResearchHiroshimaJapan
  3. 3.Department of Breast SurgeryHiroshima City HospitalHiroshimaJapan
  4. 4.Department of Anatomical PathologyHiroshima University HospitalHiroshimaJapan

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