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 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 immunomodula-tion. NK-cell activation against trastuzumab-coated HER2 thorn 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 tumorassociated 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.