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

TL;DR

A new antibody blocks immune suppression by binding to a key site on MHC-I molecules, activating NK cells and reducing tumor growth in mice.

Contribution

The study reveals the structural mechanism of an anti-MHC-I antibody blocking inhibitory NK cell receptors.

Findings

B1.23.2 binds to a conserved region on HLA-B*44:05 overlapping the KIR binding site.

Blocking inhibitory receptor interactions activates NK cells and suppresses tumor growth in a mouse model.

Abstract

Anti-major histocompatibility complex class I (MHC-I) mAbs can stimulate immune responses to tumors and infections by blocking suppressive signals delivered via various immune inhibitory receptors. To understand such functions, we determined the structure of a highly cross-reactive anti-human MHC-I mAb, B1.23.2, in complex with the MHC-I molecule HLA-B*44:05 by both cryo-electron microscopy (cryo-EM) and X-ray crystallography. Structural models determined by the two methods were essentially identical revealing that B1.23.2 binds a conserved region on the α21 helix that overlaps the killer immunoglobulin-like receptor (KIR) binding site. Structural comparison to KIR/HLA complexes reveals a mechanism by which B1.23.2 blocks inhibitory receptor interactions, leading to natural killer (NK) cell activation. B1.23.2 treatment of the human KLM-1 pancreatic cancer model in humanized (NSG-IL15) mice provides evidence of suppression of tumor growth. Such anti-MHC-I mAb that block inhibitory KIR/HLA interactions may prove useful for tumor immunotherapy.

The B1.23.2 antibody binds HLA-B*44:05 at a site that overlaps the killer Ig-like receptor binding site. It blocks inhibitory receptor interactions, leads to NK cell activation and suppresses tumor growth in a humanized mouse model.

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