The Differential Impact of Neoadjuvant Therapies on the Tumor Microenvironment, Peripheral Biomarkers, and Survival in Pancreatic Cancer: A Retrospective Cohort Study

Background/Objectives: The selection of neoadjuvant therapy for patients with non-metastatic pancreatic adenocarcinoma remains challenging. Methods: We performed a single-institution, retrospective analysis of 79 patients who underwent resection of their pancreatic adenocarcinoma after receiving neoadjuvant therapy. Clinical and pathologic data were collected. Tumor fibrosis was quantified using Masson’s trichrome staining, tumor-infiltrating lymphocytes (TIL) were evaluated by an AI-based analysis of whole-slide H&E images, and immune cell populations were quantified by multiplex immunohistochemistry. Correlation analyses were performed between neoadjuvant treatment regimen, tumor regression, immune phenotypes, and survival. Results: All patients received chemotherapy, 77% FOLFIRINOX and 23% Gemcitabine/nab-paclitaxel (Abraxane). Eighteen percent of patients went on to receive radiation. Tumor regression grade (TRG) correlated with the neoadjuvant regimen. A reduction in tumor markers and the baseline neutrophil-to-lymphocyte ratio (NLR) correlated with overall survival. Among patients with an NLR > 3.3, FOLFIRINOX conferred a survival benefit over Gemcitabine/nab-paclitaxel, and radiation trended towards improved survival. Radiation was associated with increased fibrosis and reduced infiltration of CD8+ and regulatory T cells (Tregs). Increased Tregs and PDL1+ stromal cells were associated with poor response to neoadjuvant therapy, and NLR > 3.3 correlated with increased Treg infiltration. Conclusions: Our data suggest that patients with a high baseline NLR may benefit from intensified neoadjuvant therapy with FOLFIRINOX and radiation. Combination immunotherapy targeting Tregs and the PD1/PDL1 axis may further improve outcomes.