Killing tumor cells through their surface β 2 ‐microglobulin or major histocompatibility complex class I molecules

Targeted antibody‐based therapy has been used successfully to treat cancers. Recent studies have demonstrated that tumor cells treated with antibodies specific for β 2 ‐microglobulin (β 2 M) or major histocompatibility complex (MHC) class I molecules undergo apoptosis in vitro and in vivo (mouse models). Antibodies against β 2 M or MHC class I induce tumor cell apoptosis by 1) recruiting MHC class I molecules to lipid rafts and activating LYN kinase and the signal‐transducing enzyme phospholipase C‐γ2‐dependent c‐Jun N‐terminal kinase signaling pathway and 2) expelling interleukin 6 and insulin‐like growth factor 1 receptors out of lipid rafts and inhibiting the growth and survival factor‐induced activation of the phosphatidylinositol 3‐kinase/Akt and extracellular signal‐related kinase pathways. Consequently, mitochondrial integrity is compromised, and the caspase‐9‐dependent cascade is activated in treated tumor cells. However, although β 2 M and MHC class I are expressed on normal hematopoietic cells, which is a potential safety concern, the monoclonal antibodies were selective to tumor cells and did not damage normal cells in vitro or in human‐like mouse models. These findings suggest that targeting β 2 M or MHC class I by using antibodies or other agents offers a potential therapeutic approach for β 2 M/MHC class I‐expressing malignancies. Cancer 2010. © 2010 American Cancer Society.