Low pH impairs complement-dependent cytotoxicity against IgG-coated target cells

// Ezequiel Dantas 1 , Fernando Erra Díaz 1 , Pehuén Pereyra Gerber 1 , Antonela Merlotti 1 , Augusto Varese 1 , Matías Ostrowski 1 , Juan Sabatté 1 , Jorge Geffner 1 1 Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET, Facultad de Medicina, Universidad de Buenos Aires, Argentina Correspondence to: Jorge Geffner, email: jorgegeffner@gmail.com Keywords: complement, pH, acidosis, cancer, rituximab Received: March 19, 2016     Accepted: September 20, 2016     Published: October 3, 2016 ABSTRACT Local acidosis is a common feature of allergic, vascular, autoimmune, and cancer diseases. However, few studies have addressed the effect of extracellular pH on the immune response. Here, we analyzed whether low pH could modulate complement-dependent cytotoxicity (CDC) against IgG-coated cells. Using human serum as a complement source, we found that extracellular pH values of 5.5 and 6.0 strongly inhibit CDC against either B lymphoblast cell lines coated with the chimeric anti-CD20 mAb rituximab or PBMCs coated with the humanized anti-CD52 mAb alemtuzumab. Suppression of CDC by low pH was observed either in cells suspended in culture medium or in whole blood assays. Interestingly, not only CDC against IgG-coated cells, but also the activation of the complement system induced by the alternative and lectin pathways was prevented by low pH. Tumor-targeting mAbs represent one of the most successful tools for cancer therapy, however, the use of mAb monotherapy has only modest effects on solid tumors. Our present results suggest that severe acidosis, a hallmark of solid tumors, might impair complement-mediated tumor destruction directed by mAb.