Overcoming myeloid-driven resistance to CAR T therapy by targeting SPP1

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Chimeric antigen receptor (CAR) T cell therapy shows promise but faces challenges in solid tumors.
• The tumor microenvironment (TME) significantly influences CAR T cell therapy resistance.
• The specific role of macrophages within the TME in CAR T cell therapy resistance is not fully understood.

Purpose of the Study:

• To investigate the role of macrophages in mediating resistance to CAR T cell therapy in solid tumors.
• To identify molecular mechanisms contributing to CAR T cell therapy failure in the TME.
• To explore therapeutic strategies targeting macrophages to overcome resistance.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) was performed on tumors from glioma patients receiving CAR T cell therapy.
• Integrative scRNA-seq analysis was conducted on high-grade gliomas and a syngeneic mouse model resistant to CAR T therapy.
• In vivo studies involved SPP1 blockade using an anti-SPP1 antibody in mouse models.

Main Results:

• Elevated SPP1 signatures were identified in macrophages from patients resistant to CAR T cell therapy.
• SPP1+ macrophages were found to play a dominant role in mediating resistance through suppressive pathways in the TME.
• SPP1 blockade reversed TME suppressive effects and significantly improved survival in resistant mouse models.

Conclusions:

• SPP1+ macrophages are key drivers of a suppressive TME, contributing to solid tumor resistance against CAR T cell therapy.
• Targeting SPP1 represents a potential universal strategy to enhance CAR T cell therapy efficacy in solid tumors.
• Reprogramming immune dynamics via SPP1 blockade could mitigate resistance to CAR T cell therapies.