Gastric Cancer Tumor Immune Microenvironment Landscape: Clinical Implications for Patient Outcome and Response to PD-1 Immune Checkpoint Blockade

Abstract Although gastric cancer (GC) may be classified into molecular subtypes based on the TCGA1 or ACRG2 classification, the tumor immune microenvironment (TME) remains under-evaluated in both systems. Using unsupervised clustering of gene expression signatures that describe the TME composition and properties of malignant cells from an integrated collection of 11 public cohorts, we identified five TME-based GC subtypes: mesenchymal (Mes), fibrotic (F), immune-enriched (IE), B-cell inflamed (BI), and immune-depleted (D). The GC TME subtypes provide important clinical annotation and are prognostic for patient survival. Mes and F GC were both stroma-enriched, although Mes GC also demonstrated WNT activation. Both stromal subtypes carry the worst survival, whereas alternatively, IE GC featured enhanced immune infiltration and is associated with the best prognosis. Although BI GC also demonstrated increased immune infiltration, it was associated with increased B cell signatures. The D subtype exhibited a cold immune TME with strong malignant cell properties, and with BI, these TME subtypes have intermediate survival. Microsatellite instable (MSI) GC that was IE exhibited significantly better survival than MSI GC that was not IE. The GC TME subtypes were also predictive of immune checkpoint blockade response. These newly defined GC TME molecular clusters provide a novel framework to inform clinical practice.