Changchun Du
YanBian University Medical School, China
Title: MICA immune complex formed with ï¡3 domain-specific antibody activates NK function in Fc-dependent manner
Biography
Biography: Changchun Du
Abstract
One of the mechanisms that tumors evade immune surveillance is the shedding of major histocompatibility complex (MHC) class I chain–related sequence A (MICA) and MICB from the tumor cell surface. MICA/B are ligands for the activating receptor NKG2D on NK and CD8+ T cells. MICA/B shedding reduces cell surface MICA/B and impairs NKG2D recognition. Shed MICA/B can also mask NKG2D receptor compromising the immune surveillance activity of NK cells.
Our study shows that soluble MICA (sMICA) suppressed human NK cell cytolytic activity in vitro. The NK suppression was not due to the down-regulation of cell surface NKG2D. In the presence of MICA α3 domain-specific antibody, sMICA-mediated suppression was completely blocked and NK cell cytolytic activity was restored. In contrast, restoration effect was not observed when Fc effectorless mutant antibody was employed. Furthermore, MICA immune complex pre-formed with α3 domain-specific antibody (with wild type Fc) induced significant IFN-γ secretion by NK cells in the absence of tumor cells whereas MICA immune complex pre-formed Fc effectorless antibody failed to induce IFN-γ secretion.
Our results demonstrate that MICA α3 domain-specific antibody can overcome sMICA-mediated suppression of NK cytolytic activity. Furthermore, our data suggest that the MICA immune complex formed with α3-specific antibody can activate NKG2D receptor and restore NK cell function in Fc-dependent manner. The clinical utility of α3 domain-specific MICA/B antibody may hold great promise for immunotherapy of tumors that express and shed MICA/B.