Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity

Area of Science:

• Immunology
• Cancer Biology
• Therapeutic Antibody Design

Background:

• MICA and MICB proteins are stress-induced ligands expressed by many human cancers.
• These ligands engage the Natural Killer Group 2D (NKG2D) receptor on cytotoxic lymphocytes, marking cancer cells for elimination.
• Tumors evade immune surveillance by shedding MICA and MICB, thus disabling this recognition pathway.

Purpose of the Study:

• To design antibodies that prevent the proteolytic shedding of MICA and MICB from cancer cells.
• To evaluate the efficacy of these antibodies in inhibiting tumor growth and metastasis in preclinical models.
• To elucidate the mechanisms underlying the antibody-mediated antitumor immune response.

Main Methods:

• Rational design of antibodies targeting the MICA α3 domain, a key site for proteolytic shedding.
• In vitro assessment of antibody-mediated prevention of MICA/MICB shedding from cancer cells.
• In vivo testing of antibody efficacy in immunocompetent mouse models and a humanized mouse model of melanoma metastasis.
• Analysis of immune cell activation, including Natural Killer (NK) cells, via NKG2D and CD16 Fc receptors.

Main Results:

• Antibodies successfully prevented the shedding of cell surface MICA and MICB by human cancer cells.
• Treatment with these antibodies significantly inhibited tumor growth in multiple mouse models.
• Antibody administration reduced the spread of human melanoma in a humanized mouse model.
• Antitumor immunity was primarily mediated by NK cells through the activation of NKG2D and CD16 receptors.

Conclusions:

• Targeting the MICA α3 domain with rationally designed antibodies is a viable strategy to prevent cancer immune evasion.
• This therapeutic approach reactivates NKG2D-mediated antitumor immunity by preventing ligand shedding.
• The developed antibodies demonstrate significant potential for treating cancers that evade immune detection through MICA/MICB shedding.