HER2-targeted antibody-drug conjugate induces host immunity against cancer stem cells

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Previous studies on HER2-targeted antibody-drug conjugates (ADCs) were limited to immunocompromised models, hindering the assessment of host immunity and combination therapies.
• Cancer stem cells (CSCs) represent a significant challenge in cancer treatment due to their resistance and tumorigenicity.

Purpose of the Study:

• To evaluate the efficacy of HER2-targeted ADCs in immunocompetent mouse models.
• To investigate the impact of HER2-targeted ADCs on host immunity, CSCs, and their combination with PD-L1 blockade.

Main Methods:

• Testing HER2-targeted ADCs in two immunocompetent mouse tumor models.
• Assessing tumor growth, animal survival, immune cell infiltration (CD3+, CD19+), CSC markers (ALDHhi), and immunological memory.
• Evaluating the combination therapy of ADC with anti-PD-L1 antibody.

Main Results:

• HER2-targeted ADC inhibited HER2-expressing tumors, prolonged survival, and reduced HER2+ and PD-L1+ cells.
• Combination therapy augmented efficacy, modulated immune gene expression, and increased functional tumor-infiltrating lymphocytes (TILs).
• ADC therapy reduced the number and tumorigenicity of ALDHhi CSCs, with enhanced effects when combined with anti-PD-L1.

Conclusions:

• HER2-targeted ADCs are effective against HER2-expressing tumors and reduce CSCs in immunocompetent models.
• Combination with anti-PD-L1 antibody significantly enhances therapeutic outcomes by modulating the immune microenvironment and targeting CSCs.