Enhanced antitumor immunity of VNP20009-CCL2-CXCL9 via the cGAS/STING axis in osteosarcoma lung metastasis
Ruixuan Liu1, Qi Liu1, Yuming Wang2
1Orthopedics, Ruijin Hospital, Shanghai, Shanghai, China.
Background:
Osteosarcoma (OS) with pulmonary metastasis remains challenging due to limited treatment options and the immunosuppressive nature of the tumor microenvironment (TME). Bacteria-mediated cancer therapy has emerged as a promising strategy for solid tumors but often suffers from limited efficacy due to the immunosuppressive TME, which restricts the intensity and durability of the antitumor immune response. To overcome these challenges, we engineered a novel Salmonella strain, VNP20009-CCL2-CXCL9 (VNP-C-C), leveraging the intrinsic tumor tropism of Salmonella typhimurium VNP20009 (VNP) and improving immune modulation through the recruitment of effector immune cells into the TME by the chemokines CCL2 and CXCL9.
Methods:
VNP-C-C was genetically engineered through electroporation of Plac-CCL2-CXCL9 plasmid and validated in vitro. Its antitumor efficacy, immune regulation capacity and immunomodulatory mechanisms were evaluated in vitro by using OS cell lines and immune cells (dendritic cells (DCs) and macrophages (Mφs)) and in vivo by using both immunocompromised and immunocompetent mouse models of OS lung metastasis.
Results:
VNP-C-C effectively accumulated within tumors, triggering immunogenic cell death and subsequently activating the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, thereby robustly promoting type I interferon secretion. The chemokines CCL2 and CXCL9 amplified the immune response by recruiting DCs, Mφs, and T cells to the TME. This orchestrated immune modulation reprogrammed tumor-associated macrophages to an antitumor phenotype, induced DCs maturation, significantly increased T-cell infiltration and activation within tumors, and promoted systemic T-cell memory formation in peripheral lymphoid organs. These effects collectively inhibited OS lung metastasis progression and provided survival benefits in mouse models.
Conclusion:
The engineered bacterial strain VNP-C-C effectively converts the OS lung metastatic TME into a pro-inflammatory milieu, thereby stimulating robust innate and adaptive immune responses. This offers a highly promising therapeutic avenue for OS lung metastasis with considerable translational potential in cancer immunotherapy.
Insights
Engineered bacteria VNP-C-C effectively target osteosarcoma lung metastasis by reprogramming the tumor microenvironment to stimulate potent immune responses, offering a promising new cancer immunotherapy.
Area of Science:
- Bacteriology
- Immunology
- Oncology
Background:
- Osteosarcoma (OS) with lung metastasis presents significant treatment challenges due to limited options and an immunosuppressive tumor microenvironment (TME).
- Bacteria-mediated cancer therapy shows promise but is often hindered by the immunosuppressive TME, limiting immune response intensity and durability.
Purpose of the Study:
- To engineer a novel Salmonella strain, VNP20009-CCL2-CXCL9 (VNP-C-C), to overcome TME limitations in osteosarcoma lung metastasis.
- To enhance immune modulation by recruiting effector immune cells via chemokines CCL2 and CXCL9, leveraging Salmonella's tumor tropism.
Main Methods:
- Genetic engineering of Salmonella typhimurium VNP20009 with Plac-CCL2-CXCL9 plasmid.
- In vitro validation and evaluation of antitumor efficacy and immune regulation using OS cell lines and immune cells.
- In vivo assessment in immunocompromised and immunocompetent mouse models of OS lung metastasis.
Main Results:
- VNP-C-C accumulated in tumors, induced immunogenic cell death, and activated the cGAS/STING pathway, promoting type I interferon secretion.
- CCL2 and CXCL9 recruited dendritic cells (DCs), macrophages (Mφs), and T cells, reprogramming macrophages to an antitumor phenotype and maturing DCs.
- Enhanced T-cell infiltration and activation, systemic T-cell memory formation, inhibited OS lung metastasis, and improved survival in mouse models.
Conclusions:
- The engineered VNP-C-C strain effectively converts the OS lung metastatic TME into a pro-inflammatory environment.
- This stimulates robust innate and adaptive immune responses, representing a promising therapeutic strategy for osteosarcoma lung metastasis and cancer immunotherapy.
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