MDSC suppresses T cell antitumor immunity in CAC via GPNMB in a MyD88-dependent manner
Bo Wang1, Lu Wang2, Runshi Shang2
1Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Background:
Myeloid-derived suppressor cells (MDSCs) played an essential role in tumor microenvironment to suppress host antitumor immunity and help cancer cells escape immune surveillance. However, the molecular mechanism behind tumor evasion mediated by MDSCs is not fully understood. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is considered to associate with tumor initiation, metastasis and angiogenesis. Blocking GPNMB function is a potentially valuable therapy for cancer by eliminating GPNMB+MDSCs. Our previous study has proved that blockage the MyD88 signaling with the MyD88 inhibitor, TJ-M2010-5, may completely prevent the development of CAC in mice, accompanying with downregulation of GPNMB mRNA in the inhibitor-treated mice of CAC.
Methods:
We here focus on the underlying the relationship between GPNMB function and MyD88 signaling pathway activation in MDSCs' antitumor activity in CAC.
Results:
CAC development in the mouse model is associated with expanded GPNMB+MDSCs by a MyD88-dependent pathway. The GPNMB expression on MDSCs is associated with MyD88 signaling activation. The inhibitory effect of MDSCs on T cell proliferation, activation and antitumor cytotoxicity in CAC is mediated by GPNMB in a MyD8-dependent manner.
Conclusion:
MyD88 signaling pathway plays an essential role in GPNMB+MDSC-mediated tumor immune escape during CAC development and is a promising focus for revealing the mechanisms of MDSC that facilitate immunosuppression and tumor progression.
Insights
Myeloid-derived suppressor cells (MDSCs) promote colorectal cancer (CAC) by suppressing immunity via GPNMB. Blocking MyD88 signaling inhibits GPNMB+MDSCs, offering a potential cancer therapy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Myeloid-derived suppressor cells (MDSCs) are crucial in the tumor microenvironment, suppressing anti-tumor immunity and aiding cancer immune evasion.
- Glycoprotein nonmetastatic melanoma protein B (GPNMB) is implicated in tumor initiation, metastasis, and angiogenesis, making GPNMB+MDSCs a therapeutic target.
- Previous research indicated that inhibiting MyD88 signaling can prevent colitis-associated cancer (CAC) development and downregulate GPNMB mRNA.
Purpose of the Study:
- To investigate the relationship between GPNMB function and MyD88 signaling pathway activation in MDSCs' anti-tumor activity within CAC.
- To elucidate the molecular mechanisms by which MDSCs mediate tumor immune escape in CAC.
Main Methods:
- Utilized a mouse model of colitis-associated cancer (CAC).
- Analyzed the association between GPNMB expression on MDSCs and MyD88 signaling activation.
- Assessed the impact of GPNMB on MDSC-mediated T cell suppression and anti-tumor cytotoxicity in a MyD88-dependent manner.
Main Results:
- CAC development in mice correlated with an expansion of GPNMB+MDSCs through a MyD88-dependent pathway.
- GPNMB expression on MDSCs was directly linked to MyD88 signaling pathway activation.
- GPNMB mediated the inhibitory effects of MDSCs on T cell proliferation, activation, and anti-tumor cytotoxicity in CAC, dependent on MyD88 signaling.
Conclusions:
- The MyD88 signaling pathway is integral to GPNMB+MDSC-mediated tumor immune escape during CAC.
- Targeting the MyD88 signaling pathway presents a promising strategy for understanding and overcoming MDSC-driven immunosuppression and tumor progression in CAC.
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