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

• DOI: 10.1016/j.xcrm.2024.101557
• Publication Date: 2024-05-10T14:35:46Z
• Authors: Casper W.F. van E...; Francisco X. Real; Núria Malats; Disha Vadgama; Thierry P.P. van ...; Michail Doukas; Casper H.J. van E...; Dana A.M. Mustafa
• Keywords: Male; 0303 health sciences; Macrophages; Middle Aged; Prognosis; Article; Neoadjuvant Therapy; Pancreatic Neoplasms; 03 medical and health sciences; Phenotype; Treatment Outcome; SDG 3 - Good Health and Well-being; GATA6 Transcription Factor; Biomarkers, Tumor; Humans; Female; Carcinoma, Pancreatic Ductal; Aged

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.