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Cancer Immunol Res. 2019 Aug;7(8):1280-1292. doi: 10.1158/2326-6066.CIR-18-0896. Epub 2019 Jun 12.

High Numbers of Circulating CD57+ NK Cells Associate with Resistance to HER2-Specific Therapeutic Antibodies in HER2+ Primary Breast Cancer.

Author information

1
Immunity and Infection, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain. amuntasell@imim.es jalbanell@hospitaldelmar.cat.
2
Cancer Research Program, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain.
3
Department of Medical Oncology, Hospital del Mar-CIBERONC, Barcelona, Spain.
4
Immunity and Infection, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain.
5
Department of Oncology, Hospital Clinico de Valencia-CIBERONC, Valencia, Spain.
6
Department of Pathology, IIS "Fundacion Jimenez Diaz University Hospital," Madrid, Spain.
7
Universitat Pompeu Fabra, Barcelona, Spain.
8
HLA-Immunogenetics Department, Instituto Hospital Universitario Puerta de Hierro, Majadahonda, Spain.
9
Department of Pathology, Hospital del Mar, Barcelona, Spain.
10
Biomedical Research Institute, INCLIVA, Valencia, Spain.
11
Universitat de Valencia, Valencia, Spain.
12
Cancer Research Program, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain. amuntasell@imim.es jalbanell@hospitaldelmar.cat.
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Contributed equally

Abstract

Natural killer (NK) cells can orchestrate effective antitumor immunity. The presence of tumor-infiltrating NK cells in diagnostic biopsies predicts pathologic complete response (pCR) to HER2-specific therapeutic antibodies in patients with primary breast cancer. Here, we analyzed whether diversity in circulating NK cells might influence tumor infiltration and HER2-specific therapeutic antibody efficacy. We found that numbers of circulating CD57+ NK cells inversely correlated with pCR to HER2-specific antibody treatment in patients with primary breast cancer independently of age, traditional clinicopathologic factors, and CD16A 158F/V genotype. This association was uncoupled from the expression of other NK-cell receptors, the presence of adaptive NK cells, or changes in major T-cell subsets, reminiscent of cytomegalovirus-induced immunomodulation. NK-cell activation against trastuzumab-coated HER2+ breast cancer cells was comparable in patients with high and low proportions of CD57+ NK cells. However, circulating CD57+ NK cells displayed decreased CXCR3 expression and CD16A-induced IL2-dependent proliferation in vitro Presence of CD57+ NK cells was reduced in breast tumor-associated infiltrates as compared with paired peripheral blood samples, suggesting deficient homing, proliferation, and/or survival of NK cells in the tumor niche. Indeed, numbers of circulating CD57+ were inversely related to tumor-infiltrating NK-cell numbers. Our data reveal that NK-cell differentiation influences their antitumor potential and that CD57+ NK cells may be a biomarker useful for tailoring HER2 antibody-based therapeutic strategies in breast cancer.

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