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

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 þ 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 þ breast cancer cells was comparable in patients with high and low proportions of CD57 þ NK cells. However, circulating CD57 þ NK cells displayed decreased CXCR3 expression and CD16A-induced IL2-dependent proliferation in vitro. Presence of CD57 þ 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 þ were inversely related to tumor-infiltrating NK-cell numbers. Our data reveal that NK-cell differentiation influences their antitumor potential and that CD57 þ NK cells may be a biomarker useful for tailoring HER2 antibody-based therapeutic strategies in breast cancer.

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

“…Nevertheless, several patients still display intrinsic and acquired resistance to Trastuzumab therapy (209). Interestingly, a recent study demonstrated that the number of circulating CD57 + NK cells from primary breast cancer patients receiving Trastuzumab therapy correlates with resistance to therapy (210). These NK cells showed reduced CXCR3 expression and proliferation, suggesting a phenotype exhibiting poor homing to and survival in the tumor niche.…”

New avenues for melanoma immunotherapy: Natural Killer cells?

“…88 On the other hand, the presence in the blood of mature cytotoxic CD57 + NK cells usually correlate with a lesser severe disease and a better outcome in several clinical settings, even if in some tumours they inversely correlate with the number of infiltrating NK cells and have been associated with therapy resistance. 89,90 Perturbations in the relative proportions of the two main human NK cell subsets have also been reported. 91-100 CD56 bright NK cell subset is predominant within secondary lymphoid organs, while it is poorly represented in the circulation.…”

“…On the other hand, the presence in the blood of mature cytotoxic CD57 + NK cells usually correlate with a lesser severe disease and a better outcome in several clinical settings, even if in some tumours they inversely correlate with the number of infiltrating NK cells and have been associated with therapy resistance …”

“…Notably, alterations in circulating NK cells frequency, phenotype and function have also been found in tumour patients and have been associated with the clinical outcome . So far, the analysis of peripheral blood NK cells in solid tumours patients showed an association between a suppressed functionally impaired NK cells phenotype and poor prognosis.…”

“…80 Notably, alterations in circulating NK cells frequency, phenotype and function have also been found in tumour patients and have been associated with the clinical outcome. [81][82][83][84][85][86][87][88][89][90] So far, the analysis of peripheral blood NK cells in solid tumours patients showed an association between a suppressed functionally impaired NK cells phenotype and poor prognosis. Peripheral NK cells from metastatic melanoma patients show an exhausted phenotype, with a high expression of KIRs, low levels of NCRs and downregulation of stimulating cytokines receptors, that result in functional defects in their ability to proliferate, secrete cytokines and kill target cells.…”