Novel approaches to block immune evasion mechanisms
See manuscript in Science (30 Mar 2018)
MICA and MICB (MICA/B) are expressed by many human cancers due to cellular stress and tag cells for elimination by cytotoxic lymphocytes through NKG2D receptor activation. However, tumors evade this immune recognition pathway through proteolytic shedding of MICA and MICB proteins. We rationally designed antibodies targeting the MICA α3 domain, the site of proteolytic shedding, and found that these antibodies prevented loss of cell surface MICA/B by human cancer cells.
These antibodies inhibited tumor growth in multiple fully immuno-competent mouse models and also reduced human melanoma metastases in a humanized mouse model. Anti-tumor immunity was mediated mainly by NK cells through activation of NKG2D and CD16 Fc receptors. This novel approach prevents the loss of important immunostimulatory ligands by human cancers and reactivates antitumor immunity.
This project offers opportunities for studying the role of NK cells, innate T cells and CD8 T cells in tumor immunity, and we are advancing this approach to clinical application.
de Andrade, L.F., Tay, R.E., Pan, D., Luoma, A.M., Ito, Y., Badrinath, S., Tsoucas, D., Franz, B., May, K.F., Harvey, C.J. and Kobold, S., 2018. Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell–driven tumor immunity. Science, 359(6383), pp.1537-1542.
MICA antibodies block proteolytic shedding and enable activation of NK cells through the NKG2D and CD16 receptors. This results in potent NK cell-mediated tumor immunity