Loss of SMAD4 Is Associated With Poor Tumor Immunogenicity and Reduced PD-L1 Expression in Pancreatic Cancer

Transforming Growth Factor beta (TGF beta) is a key mediator of immune evasion in pancreatic ductal adenocarcinoma (PDAC), and the addition of TGF beta inhibitors in select immunotherapy regimens shows early promise. Though the TGF beta target SMAD4 is deleted in approximately 55% of PDAC tumors, the effects of SMAD4 loss on tumor immunity have yet to be fully explored. Using a combination of genomic databases and PDAC specimens, we found that tumors with loss of SMAD4 have a comparatively poor T-cell infiltrate. SMAD4 loss was also associated with a reduction in several chemokines with known roles in T-cell recruitment, which was recapitulated using knockdown of SMAD4 in PDAC cell lines. Accordingly, JURKAT T-cells were poorly attracted to conditioned media from PDAC cells with knockdown of SMAD4 and lost their ability to produce IFN gamma. However, while exogenous TGF beta modestly reduced PD-L1 expression in SMAD4-intact cell lines, SMAD4 and PD-L1 positively correlated in human PDAC samples. PD-L1 status was closely related to tumor-infiltrating lymphocytes, particularly IFN gamma-producing T-cells, which were more abundant in SMAD4-expressing tumors. Low concentrations of IFN gamma upregulated PD-L1 in tumor cells in vitro, even when administered alongside high concentrations of TGF beta. Hence, while SMAD4 may have a modest inhibitory effect on PD-L1 in tumor cells, SMAD4 indirectly promotes PD-L1 expression in the pancreatic tumor microenvironment by enhancing T-cell infiltration and IFN gamma biosynthesis. These data suggest that pancreatic cancers with loss of SMAD4 represent a poorly immunogenic disease subtype, and SMAD4 status warrants further exploration as a predictive biomarker for cancer immunotherapy.

Automated summary

This study found that loss of SMAD4 is associated with decreased tumor immunity and reduced T-cell infiltrate in pancreatic ductal adenocarcinoma. SMAD4 loss is also correlated with reduced expression of chemokines involved in T-cell recruitment. Additionally, SMAD4 indirectly promotes PD-L1 expression by enhancing T-cell infiltration and IFN gamma biosynthesis. These findings suggest that SMAD4 status may serve as a predictive biomarker for cancer immunotherapy.