Gastric cancer mesenchymal stem cells via the CXCR2/HK2/PD-L1 pathway mediate immunosuppression

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Anti-PD-1 immunotherapy is a key treatment for advanced gastric cancer (GC).
• Drug resistance significantly limits the effectiveness of anti-PD-1 therapy in GC.
• Understanding resistance mechanisms is crucial for improving treatment outcomes.

Purpose of the Study:

• To investigate the role of gastric cancer mesenchymal stem cells (GCMSCs) in mediating resistance to anti-PD-1 immunotherapy.
• To elucidate the molecular mechanisms by which GCMSCs contribute to immune evasion and therapeutic resistance.
• To identify potential therapeutic targets for overcoming anti-PD-1 resistance in GC.

Main Methods:

• Evaluation of GCMSCs' role in anti-PD-1 resistance using in vivo xenograft mouse models (NPG^CD34+ and NCG^PBMC).
• Assessment of CD8⁺T cell infiltration and function via spectral cytometry and immunohistochemistry (IHC).
• Characterization of GCMSC-conditioned medium (GCMSC-CM) effects on GC cell lines using proteomic, secretomic, western blot, and ELISA assays.

Main Results:

• GCMSCs promote tumor immunotherapy tolerance by upregulating PD-L1 expression in GC cells, particularly under hypoxic conditions.
• GCMSC-derived IL-8 facilitates PD-L1 transcription via AKT-mediated phosphorylation of HK2 and its binding to HIF-1α.
• GCMSC-CM induces lactate overproduction, impairing CD8⁺T cell function, while IL-8/CXCR2 pathway inhibition restores anti-PD-1 efficacy.

Conclusions:

• GCMSCs contribute to anti-PD-1 resistance in advanced gastric cancer through IL-8/CXCR2 signaling, PD-L1 upregulation, and lactate production.
• Blocking the GCMSCs-derived IL-8/CXCR2 pathway represents a promising strategy to enhance anti-PD-1 immunotherapy efficacy.
• Targeting GCMSCs and their secreted factors may offer a novel therapeutic approach for overcoming resistance in advanced gastric carcinoma.