The effect of neoadjuvant therapy on immune profiling of pancreatic ductal adenocarcinoma: A prospective study of the PREOPANC-1 randomized controlled trial.

Abstract The randomized phase III trial (PREOPANC-1) that was performed in 16 centers in the Netherlands compared the effects of preoperative chemoradiotherapy (Gemcitabine and 2.4 Gy radiation) versus immediate surgery for resectable and borderline resectable pancreatic cancer. The outcomes of the secondary endpoints and predefined subgroup analyses suggest an advantage of the neoadjuvant approach. The aim of the present study was to investigate the changes in the immune microenvironment and infiltration caused by the neoadjuvant treatment. To that aim, we collected formalin-fixed, paraffin-embedded pancreatic cancer samples from all centers that participated in the PREOPANC -1 trial. We performed targeted gene expression using the PanCancer Immune Profiling panel of NanoString. Comparing 50 samples of the patient who were subjected to neoadjuvant treatment to 46 treatment-naïve samples showed a distinct genetic profile induced by the neoadjuvant therapy. More than 250 immune-related genes were significantly differentially expressed between the two groups of samples. The results indicate that neoadjuvant therapy resets the innate immune activation in the tissue samples. A significantly higher infiltration of CD14+, CD33+, CSF1R+, and CD163+, MRC1+ cells were found in samples of the neoadjuvant arm. In contrast, B cells and various subtypes of T cells like CD8+ and FOXP3+ showed a significant decrease in the same samples. Pathway analysis revealed that the neoadjuvant treatment stimulated the expression of genes related to the complement activation, chemotaxis, and wound repair, while genes related to lymphocyte activation and adaptive immune responses were dominant in the treatment-naïve arm. In conclusion, this is the first comprehensive study to describe the immune-molecular changes as a result of neoadjuvant therapy in a randomized clinical trial. The results reveal the enrichment of the myeloid compartment following neoadjuvant therapy which was significantly associated with a survival benefit for the patients. Studying the personalized effect of neoadjuvant therapy will guide choosing the appropriate combined therapy for pancreatic cancer. Citation Format: Diba Latifi, Willem de Koning, Sai ping Lau, Frederiek Grevers, Coen van Dam, Casper H. J. van Eijck, Dana A. M. Mustafa. The effect of neoadjuvant therapy on immune profiling of pancreatic ductal adenocarcinoma: A prospective study of the PREOPANC-1 randomized controlled trial [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-046.