Integrin β4-Targeted Cancer Immunotherapies Inhibit Tumor Growth and Decrease Metastasis.

Area of Science:

• Immunology
• Oncology
• Cancer Stem Cell Biology

Background:

• Integrin β4 (ITGB4) plays a crucial role in regulating cancer stem cells (CSCs).
• Targeting ITGB4 presents a novel immunotherapeutic strategy for CSCs.
• Existing immunotherapies may benefit from strategies that also target CSCs.

Purpose of the Study:

• To develop and evaluate immunologic strategies targeting ITGB4 for cancer therapy.
• To assess the efficacy of ITGB4-targeted immunotherapies in reducing CSCs and bulk tumor populations.
• To investigate the potential of combining ITGB4-targeted therapies with anti-PD-L1.

Main Methods:

• Developed ITGB4 protein-pulsed dendritic cells (ITGB4-DC) for vaccination.
• Developed anti-CD3/anti-ITGB4 bispecific antibody (ITGB4 BiAb)-armed T cells for adoptive transfer.
• Assessed immunotherapies in 4T1 mammary tumor and SCC7 head and neck squamous carcinoma mouse models, with and without anti-PD-L1 treatment.
• Evaluated tumor growth, metastasis, CSC reduction, tumor-initiating capacity, and toxicity.

Main Results:

• Both ITGB4-DC and ITGB4 BiAb-T cell immunotherapies significantly inhibited local tumor growth and metastasis in both models.
• Combination therapy with anti-PD-L1 significantly enhanced the efficacy of ITGB4-targeted immunotherapies.
• ITGB4-targeted immunotherapies induced T-cell cytotoxicity against CSCs and non-CSCs expressing ITGB4, and immune plasma-mediated killing of CSCs.
• Treatments reduced ITGB4-high CSCs and their tumor-initiating capacity, with no observed toxicity.
• Specificity was confirmed using ITGB4 knockout and ITGB4-negative cell lines.

Conclusions:

• Immunologic targeting of ITGB4, using either ITGB4-DC or ITGB4 BiAb-T cells, is a promising strategy against CSCs and bulk tumors.
• Combining ITGB4-targeted immunotherapy with anti-PD-L1 blockade further enhances therapeutic outcomes.
• ITGB4-targeted immunotherapy demonstrates potential for broad application across various tumor types expressing ITGB4 on CSCs.