Abstract C027: Perioperative immune perturbations of the metastatic microenvironment in a murine PDAC orthotopic resection model

Abstract

Abstract Surgical resection is currently the mainstay of treatment for pancreatic ductal adenocarcinoma (PDAC). After “curative intent” resection, distant metastasis occurs in majority of patients, indicating that PDAC is a systemic disease and should be considered as such at the time of surgical resection. Despite this, the effects of tumor resection on the systemic disease are not fully elucidated. Surgical trauma induces systemic immunosuppression, that can result in a “window of opportunity”, affecting metastatic seeding and outgrowth, as well as responsiveness to therapy. We used an orthotopic resection model in immunocompetent mice by performing a distal pancreatectomy and splenectomy. Using this model system, we identified outcomes similar to human disease, such as a survival benefit upon resection, systemic disease at the time of resection, and metastatic dissemination predominantly in the liver, lung, and peritoneum. Since the liver is the most common site of recurrence in human PDAC and portends a poorer prognosis than other metastases, we investigated the effect of tumor resection on the hepatic microenvironment. In surgically stressed mice undergoing sham resection and splenectomy, we identified an increase in eosinophils and a decrease in neutrophils, and these immune perturbations were augmented upon tumor resection. Time-course analysis identified transient changes in tissue resident and conventional NK cells, as well as macrophage and monocyte populations. Taken together, we have utilized a preclinical model that simulates human disease progression and response to surgery, and identified tumor resection specific alterations in the liver metastatic microenvironment. An improved understanding of the immune perturbations during this perioperative window may identify new immunotherapy strategies benefiting PDAC patients to help treat this systemic disease. Citation Format: Anthony Sorrentino, Carolina Alcantara-Hirsch, Beny Shapiro, Erica Ma, Ammar Javed, Christopher Wolfgang, Dafna Bar-Sagi. Perioperative immune perturbations of the metastatic microenvironment in a murine PDAC orthotopic resection model [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C027.