Paper

Stroma secreted IL6 selects for stem-like population and alters pancreatic tumor microenvironment by reprogramming metabolic pathways

Sharma, Nikita S, Garrido, Vanessa T, Gupta, Vineet K, Merchant, Nipun, Saluja, Ashok, Lyle, Michael, Nagathihalli, Nagaraj, Durden, Brittany, Banerjee, Sulagna, Austin Doesch, Kesh, Kousik

2020

Overview

Pancreatic adenocarcinoma is a devastating disease with an abysmal survival rate of 9%. A robust fibro-inflammatory and desmoplastic stroma, characteristic of pancreatic cancer, contributes to the challenges in developing viable therapeutic strategies in this disease. Apart from constricting blood vessels and preventing efficient drug delivery to the tumor, the stroma also contributes to aggressive biology of the cancer along with its immune-evasive microenvironment. In this study, we show that in pancreatic tumors, the developing stroma increases tumor initiation frequency in pancreatic cancer cells in vivo by enriching for CD133+ aggressive stem-like cells. Additionally, the stromal fibroblasts secrete IL6 as the major cytokine, increases glycolytic flux in the pancreatic tumor cells and increases lactate efflux in the microenvironment via activation of the STAT signaling pathway. We also show that the secreted lactate favors activation of M2 macrophages in the tumor microenvironment, which excludes CD8+ T-cells in the tumor. Our data additionally confirms that treatment of pancreatic tumors with anti-IL6 antibody results in tumor regression as well as decreased CD133+ population within the tumor. Furthermore, inhibiting the lactate efflux in the microenvironment reduces M2 macrophages, and makes pancreatic tumors more responsive to anti-PD1 therapy. This suggests that stromal IL6 driven metabolic reprogramming plays a significant role in the development of an immune evasive microenvironment. In conclusion, our study shows that targeting the metabolic pathways affected by stromal IL6 can make pancreatic tumors amenable to checkpoint inhibitor therapy. Competing Interest Statement University of Minnesota has a patent for Minnelide, which has been licensed to Minneamrita Therapeutics, LLC. AKS is the co-founder and the Chief Scientific Officer of this company. SB is a consultant with Minneamrita Therapeutics LLC and this relationship is managed by University of Miami. The remaining authors declare no conflict of interest.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Adenocarcinoma / Blood vessels / Cancer Biology / CD8 antigen / Cell activation / Drug delivery / Fibroblasts / Glycolysis / Immune checkpoint / Inflammation / Interleukin 6 / Lactic acid / Lymphocytes T / Macrophages / Metabolic pathways / Metabolism / Pancreatic cancer / PD-1 protein / Signal transduction / Stroma / Tumor cells / Tumors