Characterization and digital spatial deconvolution of the immune microenvironment of intraductal oncocytic papillary neoplasms (IOPN) of the pancreas

: Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas is a distinct entity from intraductal papillary mucinous neoplasms (IPMNs) and is considered one of the precursor lesions of pancreatic cancer. Through immunohistochemistry (IHC) and an artificial intelligence (AI)-based approach, this study aims at characterizing its immune microenvironment. Whole-slide IHC was performed on a cohort of 15 IOPNs, 2 of which harboring an associated adenocarcinoma. The following markers were tested: CD3, CD4, CD8, CD20, CD68, CD163, PD-1, PD-L1, MLH1, PMS2, MSH2, and MSH6. The main findings can be summarized as follows: (i) CD8+ T lymphocytes were the predominant immune cells (p < 0.01); (ii) the vast majority of macrophages were concurrently CD68+ and CD163+; (iii) all tumors showed an activated PD-1/PD-L1 axis, but none had mismatch repair deficiency; (iv) AI-based analysis revealed the presence of 2 distinct regions in each case, namely, Re1, localized at the center of the tumor, and Re2, located at tumor periphery; (v) the infiltrating component of the 2 invasive IOPNs showed a smaller extent of Re1 and a reduced rate of CD4+ cells, as well as a larger extent of Re2 and increased rate of CD8+ cells. IOPNs are lesions enriched in immune cells, with a predominance of CD8+ T lymphocytes and class 2 macrophages. Differently from IPMN-oncogenesis, the progression towards invasive carcinoma is accompanied by an increased rate of CD8+ lymphocytes. This finding may suggest the presence of an active self-immune surveillance in invasive IOPNs, potentially explaining, at least in part, the excellent survival rate of IOPN patients.