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.
Highlights
Natural killer (NK) cells are innate lymphocytes that can recognize antibody-coated tumor cells via the activating Fcg receptor CD16A (FcgRIIIA), leading to tumor cell death by antibody-dependent cellular cytotoxicity (ADCC) and the release of immune cell recruiting chemokines and proinflammatory cytokines [1,2,3,4,5]
Clinicopathologic characteristics of the patient cohort are presented in Table 1. pathologic complete responses (pCR) to neoadjuvant treatment was confirmed in 42% (27/64) of patients; ER status was the only conventional factor significantly associated with pCR in the studied cohort [OR 6.89; 95% confidence interval (CI), 2.06–23.05; P 1⁄4 0.002]
Despite the positive correlation between CD57þ NK cells and age (r 1⁄4 0.44 and r 1⁄4 0.46, for relative and absolute numbers, respectively, P 1⁄4 0.002), CD57þ NK-cell numbers independently associated with lower likelihood of response to HER2-specific antibodies when adjusting by age [%CD57þ NK cells OR 1.04, P 1⁄4 0.01; CD57þ NK cells/mL OR 1.006, P 1⁄4 0.03] and ER status [%CD57þ NK cells OR 1.05, P 1⁄4 0.01; CD57þ NK cells/mL OR 1.007, P 1⁄4 0.02, per unit increase] in multivariate analysis
Summary
Natural killer (NK) cells are innate lymphocytes that can recognize antibody-coated tumor cells via the activating Fcg receptor CD16A (FcgRIIIA), leading to tumor cell death by antibody-dependent cellular cytotoxicity (ADCC) and the release of immune cell recruiting chemokines and proinflammatory cytokines [1,2,3,4,5]. Indirect evidence suggests that NK cells influence the efficacy of anti-HER2 therapeutic antibodies such as trastuzumab and pertuzumab, which are the standard of care in HER2þ breast cancer. We have described an association between tumor-infiltrating NK-cell numbers in diagnostic biopsies and the achievement of pathologic complete responses (pCR) to HER2-specific antibody-based treatment in patients with HER2þ breast cancer [12]. Despite this evidence supporting a role for NK-cell–mediated ADCC in the efficacy of antiHER2 therapeutic antibodies, little is known about whether
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