GATA6 identifies an immune-enriched phenotype linked to favorable outcomes in patients with pancreatic cancer undergoing upfront surgery

This study underscores GATA6’s role in distinguishing classical and basal-like pancreatic ductal adenocarcinoma (PDAC) phenotypes. Retrospective studies associate GATA6 immunohistochemistry (IHC) expression with survival outcomes, warranting prospective validation. In a prospective treatment-naive cohort of patients with resected PDAC, GATA6 IHC proves a prognostic discriminator, associating high GATA6 expression with extended survival and the classical PDAC phenotype. However, GATA6’s prognostic significance is numerically lower after gemcitabine-based neoadjuvant chemoradiotherapy compared to its significance in patients treated with upfront surgery. Furthermore, GATA6 is implicated in immunomodulation, although a comprehensive investigation of its immunological role is lacking. Treatment-naive PDAC tumors with varying GATA6 expression yield distinct immunological landscapes. Tumors highly expressing GATA6 show reduced infiltration of immunosuppressive regulatory T cells and M2 macrophages but increased infiltration of immune-stimulating, antigen-presenting, and activated T cells. Our findings caution against solely relying on GATA6 for molecular subtyping in clinical trials and open avenues for exploring immune-based combination therapies. [Display omitted] •GATA6high IHC in treatment-naive PDAC favors survival and marks the classical phenotype•After gemcitabine-based nCRT, the prognostic relevance of GATA6 in PDAC diminishes•Treatment-naive tumors with varying GATA6 IHC yield distinct immunological landscapes•GATA6high treatment-naive tumors manifest a potent anti-tumor immune microenvironment Van Eijck et al. emphasize the prognostic value of GATA6 IHC in treatment-naive PDAC, urging caution with GATA6-based subtyping due to treatment-induced alterations in cellular phenotypes. The association between high GATA6 IHC and an anti-tumor immune environment offers a promising avenue for developing personalized immune therapies to enhance patient outcomes.