A potential role for peripheral natural killer cell activity induced by preoperative chemotherapy in breast cancer patients
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.
KeywordsBreast cancer Preoperative chemotherapy Immune response Peripheral natural killer cell (pNK) activity Transforming growth factor β Tumor microenvironment
Axillary lymph node metastasis
Cytotoxic T lymphocyte-associated protein 4
Formalin-fixed paraffin embedded
Human epidermal growth factor receptor-2
Peripheral natural killer
Tumor microenvironmental factor
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.
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.
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.
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 was obtained from all individual participants included in the study.
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