Current immunotherapies for the treatment of cancer exploit engineered T cells, a lymphocyte of the adaptive immune system. An alternative avenue is utilizing the major players of the innate immune system — natural killer (NK) cells. NK cells are innate lymphocytes that express activating receptors, including the NK group 2D (NKG2D) receptor. These NKG2D receptors recognize major histocompatibility complex (MHC) class I polypeptide–related sequence A (MICA) and MICB ligands displayed on the surface of tumor cells and pathogen-infected cells. However, tumors can disguise themselves by shedding these ligands, thereby preventing NK cells from detecting and destroying the tumor cells. In fact, high serum concentrations of shed MICA are correlated with disease progression in many human cancers.
In a recent study lead by researchers at the Dana Farber Cancer Institute, antibodies were engineered to bind to key epitopes on MICA and MICB. By binding these sites required for initiation of MICA and MICB shedding, the antibodies prevented the loss of these ligands in a highly specific manner. By locking MICA and MICB onto the surface of tumor cells, NK cells were able to effectively drive antitumor immunity through activation of the NKG2D receptor and antibody-dependent cell-mediated cytotoxicity via CD16 Fc receptors.
This represents a clever approach to improve NK cell recognition of tumor cells. Harnessing the unique capabilities of the innate immune system overcomes common safety concerns with other cell therapies, thereby extending the range of immunotherapies beyond T cells. The article, titled “Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell–driven tumor immunity,” was published in Science.