Genetic variation of human neutrophil Fcγ receptors and SIRPα in antibody-dependent cellular cytotoxicity towards cancer cells.

The efficacy of cancer therapeutic antibodies varies considerably among patients. Anticancer antibodies act through different mechanisms, including antibody-dependent cellular cytotoxicity (ADCC) triggered via Fc gamma receptors (Fc gamma R). This phagocyte ADCC can be promoted by interference with CD47-SIRPa interactions, but the magnitude of this enhancement also varies among individuals. Both Fc gamma R and SIRP alpha display considerable genetic variation, and we investigated whether this explains some of the variability in ADCC. Because of linkage disequilibrium between Fc gamma R variants the interpretation of previous reports suggesting a potential link between Fc gamma R polymorphisms and ADCC has been troublesome. We performed an integrated genetic analysis that enables stratification. ADCC by activated human neutrophils towards Trastuzumab-coated breast cancer cells was predominantly dependent on Fc gamma RIIa. Neutrophils from individuals with the Fc beta RIIa-131H polymorphic variant displayed significantly higher killing capacity relative to those with Fc gamma RIIa-131R. Furthermore, ADCC was consistently enhanced by targeting CD47-SIRP alpha interactions, and there were no significant functional differences between the two most prevalent SIRP alpha polymorphic variants. Thus, neutrophil ADCC capacity is directly related to the Fc gamma RIIa polymorphism, and targeting CD47-SIRP alpha interactions enhances ADCC independently of Fc gamma R and SIRP alpha genotype, thereby further suggesting that CD47-SIRP alpha interference might be a generic strategy for potentiating the efficacy of antibody therapy in cancer.