Targeting P2RY2 reprograms tumor immunity and inhibits tumor growth in non-small cell lung cancer

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Non-small cell lung cancer (NSCLC) progression is linked to immunosuppressive M2 macrophages and reduced CD8+ T cell infiltration.
• The tumor microenvironment (TME) plays a critical role in regulating anti-tumor immunity and immunotherapy response.
• Understanding molecular drivers of immune suppression in NSCLC is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the role of the purinergic P2Y2 receptor (P2RY2) in regulating M2 macrophage enrichment and CD8+ T cell exclusion in the NSCLC TME.
• To assess the therapeutic potential of targeting P2RY2 in preclinical models of NSCLC.

Main Methods:

• Analysis of P2RY2 expression in human NSCLC tissues and correlation with clinical parameters (TNM stage, survival).
• Pharmacological inhibition and genetic deletion of P2RY2 in syngeneic and autochthonous mouse models of NSCLC.
• Flow cytometry and immunohistochemistry to assess immune cell populations (M2 macrophages, CD8+ T cells) within the TME.
• Co-culture experiments to evaluate the effect of P2RY2 on macrophage proliferation.

Main Results:

• P2RY2 expression is significantly elevated in NSCLC and associated with advanced TNM stage and poorer survival.
• Inhibition or genetic deletion of P2RY2 led to decreased M2 macrophage abundance and increased CD8+ T cell infiltration in the TME.
• Targeting P2RY2 resulted in reduced tumor burden in preclinical NSCLC models.
• Macrophages are the primary P2RY2-expressing cells in the TME, and P2RY2 promotes tumor-educated macrophage proliferation.

Conclusions:

• P2RY2 is a key regulator of the immunosuppressive TME in NSCLC by promoting M2 macrophage enrichment and CD8+ T cell exclusion.
• Targeting P2RY2 demonstrates significant anti-tumor efficacy in preclinical models.
• P2RY2 represents a promising novel immunotherapeutic target for NSCLC treatment.