CXCR4-modified CAR-T cells suppresses MDSCs recruitment via STAT3/NF-κB/SDF-1α axis to enhance efficacy against
Ruixin Sun1, Yansha Sun2, Chuanlong Wu3
1State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China; Department of Laboratory Medicine, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China.
Abstract:
Claudin18.2 (CLDN18.2)-specific chimeric antigen receptor (CAR-T) cells displayed limited efficacy in CLDN18.2-positive pancreatic ductal adenocarcinoma (PDAC). Strategies are needed to improve the trafficking capacity of CLDN18.2-specific CAR-T cells. PDAC has a unique microenvironment that consists of abundant cancer-associated fibroblasts (CAFs), which could secrete stromal cell-derived factor 1α (SDF-1α), the ligand of CXCR4. Then, we constructed and explored CLDN18.2-targeted CAR-T cells with CXCR4 co-expression in treating immunocompetent mouse models of PDAC. The results indicated that CXCR4 could promote the infiltration of CAR-T cells and enhance their efficacy in vivo. Mechanistically, the activation of signal transducer and activator of transcription 3 (STAT3) signaling was impaired in CXCR4 CAR-T cells, which reduced the release of inflammatory factors, such as tumor necrosis factor-α, IL-6, and IL-17A. Then, the lower release of inflammatory factors suppressed SDF-1α secretion in CAFs via the nuclear factor κB (NF-κB) pathway. Therefore, the decreased secretion of SDF-1α in feedback decreased the migration of myeloid-derived suppressor cells (MDSCs) in tumor sites. Overall, our study demonstrated that CXCR4 CAR-T cells could traffic more into tumor sites and also suppress MDSC migration via the STAT3/NF-κB/SDF-1α axis to obtain better efficacy in treating CLDN18.2-positive pancreatic cancer. Our findings provide a theoretical rationale for CXCR4 CAR-T cell therapy in PDAC.
Insights
Chimeric antigen receptor (CAR)-T cells targeting Claudin18.2 (CLDN18.2) show improved pancreatic cancer treatment. Co-expressing CXCR4 enhances CAR-T cell infiltration and suppresses myeloid-derived suppressor cells, boosting therapeutic efficacy.
Area of Science:
- Immunology
- Oncology
- Cell Therapy
Background:
- Claudin18.2 (CLDN18.2)-specific CAR-T cells have limited efficacy in CLDN18.2-positive pancreatic ductal adenocarcinoma (PDAC).
- Pancreatic cancer microenvironments feature cancer-associated fibroblasts (CAFs) secreting stromal cell-derived factor 1α (SDF-1α), the CXCR4 ligand.
- Improved CAR-T cell trafficking is crucial for effective PDAC treatment.
Purpose of the Study:
- To construct and evaluate CLDN18.2-targeted CAR-T cells co-expressing CXCR4 for PDAC treatment.
- To investigate the mechanisms underlying the enhanced efficacy of CXCR4-modified CAR-T cells in vivo.
- To explore the potential of CXCR4 CAR-T cell therapy in CLDN18.2-positive pancreatic cancer.
Main Methods:
- Construction of CLDN18.2-targeted CAR-T cells with CXCR4 co-expression.
- Evaluation of CAR-T cell infiltration and anti-tumor efficacy in immunocompetent mouse models of PDAC.
- Analysis of signaling pathways including STAT3 and NF-κB, and assessment of inflammatory factor and SDF-1α secretion.
Main Results:
- CXCR4 co-expression significantly promoted CAR-T cell infiltration into PDAC tumors.
- CXCR4 CAR-T cells demonstrated enhanced anti-tumor efficacy in vivo.
- Mechanistically, CXCR4 CAR-T cells impaired STAT3 signaling, reduced inflammatory factors, suppressed CAF SDF-1α secretion via NF-κB, and decreased myeloid-derived suppressor cell (MDSC) migration.
Conclusions:
- CXCR4 CAR-T cells exhibit improved tumor trafficking and therapeutic efficacy in CLDN18.2-positive PDAC.
- The STAT3/NF-κB/SDF-1α axis is a key mediator of CXCR4 CAR-T cell function, suppressing MDSC infiltration.
- This study provides a strong rationale for utilizing CXCR4-modified CAR-T cells in pancreatic cancer therapy.
