Chimeric antigen receptor-modified macrophages trigger systemic anti-tumour immunity

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Lipid droplet high (LD^hi) immunosuppressive cells are accumulating in tumor tissues.
• These cells play a role in immune tolerance within the tumor microenvironment.

Purpose of the Study:

• To track and characterize LD^hi immunosuppressive cells.
• To develop targeted therapies against these immunosuppressive cells.
• To investigate the role of CCR7 in immune tolerance.

Main Methods:

• Phenotypic profiling of LD^hi immune cell populations (CD19⁺, CD11b⁺, Ly6G⁺) in a syngeneic tumor model.
• Utilizing a contact-dependent reporter system to identify LD^hi CCR7^hi cells.
• Engineering chimeric antigen receptor-modified macrophages (CAR-Ms) targeting CCR7.
• Evaluating the efficacy of CCR7-targeted CAR-Ms in vivo.

Main Results:

• LD^hi CD19⁺, LD^hi CD11b⁺, and LD^hi Ly6G⁺ populations were identified in spleen, thymus, and tumor tissues.
• A LD^hi CCR7^hi immunosuppressive cell population was discovered that migrates from tumors to the spleen and thymus.
• CCR7-targeted CAR-Ms, utilizing MerTK, demonstrated tumor cell cytotoxicity.
• In vivo, CCR7-targeted CAR-Ms suppressed tumor growth, prevented metastasis, and induced systemic anti-tumor immunity by inhibiting LD^hi CCR7^hi cell migration.

Conclusions:

• CCR7 plays a critical role in tumor cell-induced immune tolerance by facilitating the migration of immunosuppressive cells.
• Targeting CCR7-positive immunosuppressive cells with CAR-Ms is a promising therapeutic strategy for cancer treatment.
• Inhibiting the migration of LD^hi CCR7^hi cells can restore systemic anti-tumor immunity.