High numbers of circulating CD57+ NK cells associate with resistance to HER2-specific therapeutic antibodies in HER2+ primary breast cancer

Natural Killer (NK) cells can orchestrate effective antitumor immunity. The presence of tumor-infiltrating NK cells in diagnostic biopsies predicts pathological complete response (pCR) to HER2-specific therapeutic antibodies in primary breast cancer patients. 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 primary breast cancer patients independently of age, traditional clinicopathological 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. Trastuzumab-induced NK-cell activation against 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 to 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. Absence of tumor-infiltrating NK cells in these tumors may underlie the association with resistance to HER2-specific therapeutic antibodies. 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.