Specifically blocking αvβ8-mediated TGF-β signaling to reverse immunosuppression by modulating macrophage...

Area of Science:

• Immunology
• Oncology
• Structural Biology

Background:

• Targeting the TGF-β pathway in cancer is challenging due to TGF-β's context-dependent roles.
• Integrin αvβ8, a key TGF-β activator, shows anti-tumor effects when targeted by antibodies, but its expression and mechanism are debated.

Purpose of the Study:

• To investigate the expression profile of integrin αvβ8 in human tumors.
• To develop and characterize a novel anti-αvβ8 antibody for cancer therapy.
• To elucidate the anti-tumor mechanisms and therapeutic potential of targeting αvβ8.

Main Methods:

• Single-cell RNA sequencing to determine αvβ8 expression.
• Development and in vitro characterization of an anti-αvβ8 antibody (130H2).
• Cryo-EM for structural analysis of antibody-integrin interaction.
• In vivo efficacy studies in syngeneic mouse models, including combination therapy with PD-1 antibodies.
• Analysis of αvβ8 expression in human PBMCs and its effect on macrophage polarization.
• Pharmacokinetic studies in non-human primates.

Main Results:

• Integrin αvβ8 is expressed in specific tumors and tumor-infiltrating macrophages.
• The anti-αvβ8 antibody 130H2 exhibits high affinity, specificity, and blocking activity, interacting solely with the β8 subunit.
• In vivo, 130H2 treatment inhibited tumor growth, reduced immunosuppression, and promoted immune cell infiltration.
• Combination therapy with PD-1 antibodies demonstrated synergistic anti-tumor effects.
• The antibody modulated macrophage polarization, and tumors with higher αvβ8 expression responded better.
• Favorable pharmacokinetics were observed.

Conclusions:

• Integrin αvβ8 is expressed in certain tumors and tumor-associated macrophages, making it a viable therapeutic target.
• Targeting αvβ8 with antibody 130H2 effectively inhibits tumor growth by reprogramming macrophages and enhancing anti-tumor immunity.
• Combination of αvβ8 blockade with PD-1 inhibition significantly improves efficacy, particularly in immune-excluded tumors.
• These findings support the clinical development of αvβ8-targeting antibodies for cancer treatment.