Structural basis of anti-MHC-I antibody blocking of inhibitory NK cell receptors in tumor immunity 2299676

Abstract Introduction Anti-MHC-I mAbs in human and murine systems can stimulate immune responses to tumors and infections by competitively blocking inhibitory signals delivered by MHC-I-specific inhibitory receptors of several inflammatory cell types (Panda, A.K. et al. J Immunol, 2020). Previous work showed that anti-MHC-I mAbs could activate immune responses by blocking the interactions of HLA with inhibitory receptors like leukocyte immunoglobulin-like receptors LILR (Panda, A.K. et al. Cancer Immunol. Res., 2025). Methods Here, we determined the structure of a broadly reactive anti-human MHC-I mAb, B1.23.2, in complex with the MHC-I molecule HLA-B*44:05 by both X-ray crystallography and cryo-electron microscopy (cryo-EM) (Jiang J. et al. Commun. Biol. 2025, in review) Results The determined structure revealed that B1.23.2 binds to a conserved region on the MHC-I molecule that overlaps with the binding sites for killer immunoglobulin-like receptors (KIRs), indicating the binding competition between anti-MHC-I mAb and KIRs. These studies prompted experiments evaluating B1.23.2 treatment in the human KLM-1 pancreatic cancer model using humanized (NSG-IL15) mice, providing evidence of tumor growth suppression by these anti-MHC-I mAbs. Conclusion We proposed a mechanism of anti-MHC-I mAb blocking NK cell inhibitory receptors, which is distinct from other checkpoint mAb mechanisms. These results provide new insights into the structural basis of how anti-MHC-I antibodies can be used in cancer immunotherapy by specifically targeting inhibitory receptor interactions. Funding Source This work was supported by the Division of Intramural Research, NIAID, NIH. Topic Categories Classical and Non-Classical Antigen Presenting Cells (APC)