Enhancing CAR-T Cell Efficacy in Solid Tumors by Inhibiting CCL5/VEGF-Mediated Angiogenesis

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor-modified T cells (CAR-T) are effective against blood cancers but show limited efficacy in solid tumors.
• The tumor microenvironment (TME) presents non-specific barriers to CAR-T cell function.

Purpose of the Study:

• To investigate the dose-dependent impact of CAR-T cells on solid tumor growth.
• To elucidate the mechanisms by which CAR-T cells influence the TME and tumor progression.
• To identify strategies for enhancing CAR-T cell efficacy in solid tumors.

Main Methods:

• Utilized multiple mouse models to assess CAR-T cell therapy.
• Analyzed the dual role of tumor-infiltrating CAR-T cells, including cytokine and chemokine production.
• Investigated the role of CCL5 in promoting tumor growth and angiogenesis.
• Tested combination therapy using CCL5-knockout CAR-T cells and CCR5 inhibitors.

Main Results:

• CAR-T cell impact on tumor growth is dose-dependent, ranging from promotion to inhibition.
• Tumor-infiltrating CAR-T cells release antitumor molecules (IFN-γ, TNF-α) but also CCL5.
• CCL5 produced by CAR-T cells promotes tumor growth by inducing VEGF and angiogenesis.
• Combination therapy with CCL5-knockout CAR-T cells and maraviroc significantly improved antitumor efficacy.

Conclusions:

• CCL5-mediated protumor activity is a key limitation for CAR-T cell therapy in solid tumors.
• Targeting CCL5 and its receptor CCR5 offers a promising strategy to enhance CAR-T cell efficacy.
• These findings pave the way for improved combination therapies against solid tumors.