Abstract A30: Chronic inflammation induces severe stromal damage and early pancreatic tumors in mice with activated Akt1 and KRas

Abstract

Abstract Inflammation and the immune environment is implicated as a risk for pancreatic ductal adenocarcinoma (PDAC), especially in chronic conditions. However, a mechanistic link is unknown. Recently, radiotherapy followed by immune checkpoint inhibitors are being tested and show promising results, thereby introducing immune modulation as a new investigational area for the treatment of pancreatic cancer. A potential barrier is that pancreatic fibrosis and desmoplastic reactivity are common characteristics of PDAC and makes therapeutic delivery difficult. To define how inflammation and desmoplasia effects the immune-pancreatic stromal environment and progression of PDAC, we have chronically injected caerulein into genetically engineered mice that we previously showed spontaneously develop PDAC through the cooperation of mutant active Akt1 and KRas. We show that injected Akt1Myr/KRasG12D mice have increased tissue remodeling, stellate cell activation, collagen production, and mucin production when compared to KRasG12D mice. They also have increased ductal proliferation, accelerated tumor formation, and increased immune cell infiltration in the pancreas ducts and stroma compared to control PBS- and caerulein-injected KRasG12D mice. Pro-inflammatory cytokines and macrophages likely activate stellate cells, which in turn facilitate additional cytokines to enhance a pro-tumor immune environment. Other than macrophages, the role that innate immune cells contribute to pancreatic cancer has not been well studied. Ongoing studies will delineate the immune cell infiltration, cytokine levels, and the effect on tumor formation in double mutant Akt1Myr/KRasG12D mice. Understanding the mechanisms by which inflammation affects tumor formation can lead to strategies to inhibit pro-tumor changes, impede PDAC development and improve overall patient survival. Citation Format: Sarah B. Gitto, Kathryn A. Cline, Amr S. Khaled, Deborah A. Altomare.{Authors}. Chronic inflammation induces severe stromal damage and early pancreatic tumors in mice with activated Akt1 and KRas. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A30.