Spatial heterogeneity of MDSCs mediated by ANXA1-FPRs signaling drives immune suppression in OSCC progression
Fengtian Li1,2,3, Yunwei Han4, Farong Ou5
1School of Biosciences and Technology, Chengdu Medical College, Chengdu, China. lft549544593@live.com.
Abstract:
Limited efficacy of immunotherapy in oral squamous cell carcinoma (OSCC) is driven by an immunosuppressive tumor microenvironment, yet the role of intratumoral spatial heterogeneity in immune responses remains unclear. Here, we employ single-cell and spatial transcriptomics to dissect the cellular composition and spatial organization of OSCC. We find CD8+ T cells are spatially localized yet functionally suppressed in late-stage OSCC, while myeloid-derived suppressor cells (MDSCs) transition from tumor core infiltration in early-stage OSCC to marginal localization with CD8+ T cells in advanced stages. ANXA1-FPR2 signaling mediates tumor-MDSCs communications, sustaining MDSCs recruitment and immune suppression. Disrupting ANXA1-FPR2 with an antagonist enhances the efficacy of immune checkpoint blockade therapy in OSCC mouse models. These findings reveal the spatial dynamics of MDSCs as key modulators of immune suppression and therapeutic resistance, offering a promising target to improve immunotherapy outcomes in OSCC.
Insights
Immunotherapy is limited in oral squamous cell carcinoma (OSCC) due to an immunosuppressive tumor microenvironment. Targeting ANXA1-FPR2 signaling with myeloid-derived suppressor cells (MDSCs) can overcome resistance and improve treatment efficacy.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Immunotherapy efficacy in oral squamous cell carcinoma (OSCC) is hindered by an immunosuppressive tumor microenvironment.
- The impact of intratumoral spatial heterogeneity on immune responses in OSCC is not well understood.
Purpose of the Study:
- To investigate the cellular composition and spatial organization within OSCC.
- To elucidate the role of spatial heterogeneity in immune suppression and therapeutic resistance in OSCC.
Main Methods:
- Single-cell and spatial transcriptomics were utilized to analyze OSCC samples.
- Cellular composition, spatial localization, and intercellular communication pathways were dissected.
Main Results:
- CD8+ T cells were found to be spatially localized but functionally suppressed in late-stage OSCC.
- Myeloid-derived suppressor cells (MDSCs) shifted from tumor core to marginal localization, interacting with CD8+ T cells in advanced stages.
- ANXA1-FPR2 signaling was identified as a key mediator of tumor-MDSC communication, driving immune suppression.
Conclusions:
- Spatial dynamics of MDSCs are critical regulators of immune suppression and immunotherapy resistance in OSCC.
- Disrupting ANXA1-FPR2 signaling enhances the efficacy of immune checkpoint blockade therapy in OSCC models.
- Targeting ANXA1-FPR2 signaling presents a promising strategy to improve immunotherapy outcomes in oral squamous cell carcinoma.
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