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

  • Aura Muntasell
    1Immunity and Infection, IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Barcelona, Spain.
  • Sònia Servitja
    2Cancer Research Program, IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Barcelona, Spain.
  • Mariona Cabo
    1Immunity and Infection, IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Barcelona, Spain.
  • Begoña Bermejo
    4Department of Oncology, Hospital Clinico de Valencia-CIBERONC, Valencia, Spain.
  • Sandra Pérez-Buira
    5Department of Pathology, IIS “Fundacion Jimenez Diaz University Hospital,” Madrid, Spain.
  • Federico Rojo
    5Department of Pathology, IIS “Fundacion Jimenez Diaz University Hospital,” Madrid, Spain.
  • Marcel Costa-García
    6Universitat Pompeu Fabra, Barcelona, Spain.
  • Oriol Arpí
    2Cancer Research Program, IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Barcelona, Spain.
  • Manuela Moraru
    7HLA-Immunogenetics Department, Instituto Hospital Universitario Puerta de Hierro, Majadahonda, Spain.
  • Laia Serrano
    8Department of Pathology, Hospital del Mar, Barcelona, Spain.
  • Ignasi Tusquets
    2Cancer Research Program, IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Barcelona, Spain.
  • María Teresa Martínez
    4Department of Oncology, Hospital Clinico de Valencia-CIBERONC, Valencia, Spain.
  • Gemma Heredia
    6Universitat Pompeu Fabra, Barcelona, Spain.
  • Andrea Vera
    1Immunity and Infection, IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Barcelona, Spain.
  • María Martínez-García
    2Cancer Research Program, IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Barcelona, Spain.
  • Laura Soria
    1Immunity and Infection, IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Barcelona, Spain.
  • Laura Comerma
    8Department of Pathology, Hospital del Mar, Barcelona, Spain.
  • Sara Santana-Hernández
    1Immunity and Infection, IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Barcelona, Spain.
  • Pilar Eroles
    4Department of Oncology, Hospital Clinico de Valencia-CIBERONC, Valencia, Spain.
  • Ana Rovira
    2Cancer Research Program, IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Barcelona, Spain.
  • Carlos Vilches
    7HLA-Immunogenetics Department, Instituto Hospital Universitario Puerta de Hierro, Majadahonda, Spain.
  • Ana Lluch
    4Department of Oncology, Hospital Clinico de Valencia-CIBERONC, Valencia, Spain.
  • Joan Albanell
    2Cancer Research Program, IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Barcelona, Spain.
  • Miguel López-Botet
    1Immunity and Infection, IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Barcelona, Spain.

抄録

<jats:title>Abstract</jats:title><jats:p>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.</jats:p>

収録刊行物

  • Cancer Immunology Research

    Cancer Immunology Research 7 (8), 1280-1292, 2019-08-01

    American Association for Cancer Research (AACR)

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