| Sumario: | Context.--Alterations in the tumor microenvironment affect the response to immunotherapy and are associated with clinical outcomes. However, the role of B7 family checkpoint molecules in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Objective.--To investigate the expression of programmed death ligand-1 (PD-L1), B7 homolog 3 (B7-H3), and B7 homolog 4 (B7-H4) and the association of these molecules with pathologic features, DNA damage repair (DDR) molecules, immune infiltrates, and survival in PDAC. Design.--The expression of B7 family molecules, densities of immune cells, and DDR status were evaluated by using immunohistochemical assays in tissue microarrays. Results.--Positive PD-L1 expression on tumor cells (TCs) and stromal cells (SCs) was observed in 30.3% (80 of 264) and 20.5% (54 of 264) of patients, respectively, whereas B7-H3 showed positivity in 81.3% (195 of 240) and 87.9% (211 of 240) of patients, respectively. B7-H4 was detected exclusively in tumor cells, with a positivity rate of 76.0% (193 of 254). PD-L1 on TCs was an independent predictor of worse disease-free survival, whereas B7-H3 on TCs was an independent factor of improved survival. The prognostic significance of PD-L1 was more discriminative in lymph node--negative, p53--wild-type, and low-BRCA1/2-expression tumors. B7-H3 on SCs was negatively correlated with CD45RO T cells, whereas PD-L1 on SCs was related to high densities of CD3, CD4, CD8, CD45RO, and Foxp3 T cells and B7-H4 was more common in tumors with a low CD8 status. Conclusions.--We identified B7 family checkpoint molecules as potentially prognostic indicators, combined with different DDR molecular statuses and complex immune infiltrates, in PDAC.
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