Antibody Blockade of Ly49/MHC-I interactions enhances Innate and Adaptive Immunity Against Cancer Metastasis

Area of Science:

• Immunology
• Cancer Biology
• Structural Biology

Background:

• Antibody-mediated blockade of innate receptor-MHC-I interactions enhances anti-tumor immunity, especially in cancers resistant to checkpoint inhibitors.
• The pan anti-MHC-I monoclonal antibody M1/42 targets MHC-I interactions with Ly49 receptors on murine NK cells.

Purpose of the Study:

• To investigate the effects of M1/42 on immune cell activation and anti-tumor activity.
• To assess M1/42's efficacy against checkpoint inhibitor-resistant pancreatic ductal adenocarcinoma (PDAC) and B16F10 melanoma.
• To elucidate the structural mechanism of M1/42's interaction with MHC-I.

Main Methods:

• Administration of M1/42 to mice, followed by assays for immune cell proliferation and activation.
• Assessment of anti-tumor activity in PDAC and B16F10 melanoma models.
• Cryo-electron microscopy (cryo-EM) and X-ray crystallography to study M1/42 complexed with H2-D^d.

Main Results:

• M1/42 robustly activated NK cells, memory T cells, dendritic cells, and macrophages, independent of Fcγ receptors.
• M1/42 significantly restricted tumor growth and metastasis, increasing CD8⁺ T cell infiltration and reducing regulatory T cells.
• Structural analysis revealed M1/42's effect on Ly49/MHC-I interactions was not due to direct steric competition.

Conclusions:

• M1/42 unleashes coordinated innate and adaptive immune responses, overcoming tumor-induced immunosuppression and resistance to checkpoint blockade.
• This approach offers a potential paradigm shift for treating metastatic cancers that evade immune surveillance via MHC-I modulation.