PD-1/PD-L1-Associated Immunoarchitectural Patterns Stratify Pancreatic Cancer Patients into Prognostic/Predictive...

Immunotherapy, including PD-1/PD-L1 agonists, has shown limited efficacy in pancreatic ductal adenocarcinoma (PDAC). We examined the PD-1/PD-L1 expression and immunoarchitectural features by automated morphometric analysis using multiplex immunofluorescence and 118 microsatellite-stable, treatment-naïve, surgically resected PDACs (study cohort). Five microsatellite-instable cases were stained in parallel (MSI cohort). Molecular analysis was additionally performed. An independent PDAC cohort (n = 226) was immunostained for PD-L1 and used as a validation cohort. PD-L1 expression on tumor cells (TC) and/or immune cells (IC) was present in 32% and 30% of the study and validation cohorts, respectively, and assigned into one of four patterns: "adaptive-1" (TC: 0, IC > 1%), "adaptive-2" (TC > 1% to < 25%, IC > 1%), "constitutive" (TC ≥ 25%, IC: 0), and "combined" (TC ≥ 25%, IC > 1%). "Constitutive" tumors were characterized by reduced numbers of all ICs and poor outcome. In contrast, "adaptive-1" tumors exhibited abundant T cells, including high counts of cytotoxic CD3⁺CD8⁺ and PD-1⁺CD3⁺CD8⁺ cells, but low counts of PD-L1⁺CD3⁺CD8⁺ cells and associated with the best outcome. "Adaptive-2" tumors displayed higher proportions of PD-L1⁺CD3⁺CD8⁺ T cells and tumor-associated macrophages (CD68⁺ and CD68⁺CD206⁺) compared with "adaptive-1" tumors. In the "combined" pattern, extensive PD-L1 expression on TCs was accompanied by increased numbers of T cells and improved overall survival. ICs were closer to PD-L1^- than to PD-L1⁺ PDAC cells. TP53 and PIK3CA alterations tended to be more frequent in PD-L1⁺ tumors. The 5 MSI cases were PD-L1^- The distinct PD-1/PD-L1-associated immunoarchitectural patterns underpin the heterogeneity of the immunologic responses and might be used to inform patient outcomes and therapeutic decisions in pancreatic cancer.