Stromal-Derived IL-8 Promotes M2 Macrophage Polarization via the RhoA/MRTF-A/SRF Transcriptional Axis to Impair CD8+
1Department of Oncology, School of Medicine, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University, Shanghai, China.
Background:
Building upon our previous finding that tumor-derived lactate activates DESMIN+ cancer-associated fibroblasts (CAFs) to secrete interleukin-8 (IL-8), this study investigates the downstream IL-8/C-X-C motif chemokine receptor 2 (CXCR2) axis in CAF-mediated macrophage polarization and lung cancer (LC) progression.
Methods:
Orthotopic and subcutaneous tumor models were established in immunocompetent and immunodeficient mice using LC, CAFs, or murine tumor organoids (MTO). Global and myeloid-specific Cxcr2 knockout models, in vitro co-cultures (macrophages, CD8+ T cells, and tumor cells), and patient-derived organoid (PDO) systems were employed.
Results:
DESMIN+ CAFs were the predominant source of IL-8 and promoted tumorigenesis and M2-like macrophage accumulation via the IL-8/CXCR2 axis. Genetic deletion of Cxcr2, myeloid-specific knockout, or pharmacological blockade reduced M2-like macrophage polarization through the PI3K/AKT/RhoA/MRTF-A/SRF pathway, restored CD8+ T cell effector function, and suppressed tumor progression. CXCR2 blockade also synergized with chemotherapy and anti-PD-L1 immunotherapy in murine models. In human PDO co-cultures with matched DESMIN+ CAFs and autologous CD8+ T cells, CXCR2 inhibition attenuated M2-like polarization and enhanced T cell-mediated killing of tumor organoids.
Conclusion:
DESMIN+ CAFs drive an immunosuppressive tumor microenvironment in LC through IL-8/CXCR2 signaling and downstream MRTF-A activation. Targeting this axis represents a promising strategy to overcome treatment resistance in LC.
Insights
Tumor-associated DESMIN+ fibroblasts secrete IL-8, activating the IL-8/CXCR2 axis. This drives immunosuppression and lung cancer progression, but targeting this axis may overcome treatment resistance.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Tumor-derived lactate activates DESMIN+ cancer-associated fibroblasts (CAFs) to secrete IL-8.
- This study investigates the IL-8/CXCR2 axis in CAF-mediated macrophage polarization and lung cancer (LC) progression.
Purpose of the Study:
- To elucidate the role of the IL-8/CXCR2 axis in CAF-mediated macrophage polarization and LC progression.
- To evaluate the therapeutic potential of targeting this axis in LC.
Main Methods:
- Utilized orthotopic and subcutaneous tumor models in immunocompetent and immunodeficient mice.
- Employed global and myeloid-specific Cxcr2 knockout models, in vitro co-cultures, and patient-derived organoid (PDO) systems.
- Investigated the PI3K/AKT/RhoA/MRTF-A/SRF pathway and assessed CD8+ T cell function.
Main Results:
- DESMIN+ CAFs are a major source of IL-8, promoting tumorigenesis and M2-like macrophage accumulation via IL-8/CXCR2.
- Cxcr2 deletion or blockade reduced M2-like polarization, restored CD8+ T cell function, and suppressed tumor progression.
- CXCR2 blockade synergized with chemotherapy and anti-PD-L1 therapy, and enhanced T cell-mediated killing in human PDOs.
Conclusions:
- DESMIN+ CAFs promote an immunosuppressive tumor microenvironment in LC via IL-8/CXCR2 signaling and MRTF-A activation.
- Targeting the IL-8/CXCR2 axis is a promising strategy to overcome LC treatment resistance.
