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

Abstract

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.

10 years of Cell Death & Disease

“…However, many cancer patients do not respond initially or develop secondary resistance. In their review, Cerezo and Rocchi 2 discuss how targeting metabolism could help modulate antitumor immunity and exploring the possibility that the metabolic reprogramming in cancer cells may represent a way to favor the antitumor response 7 . Another key factor in the development of cancer tumor resistance to therapy is discussed in the review by Dong et al 3 highlighting the contribution of exosomes to drug resistance in breast cancer.…”

A novel fatty acid metabolism‐related gene signature predicts the prognosis, tumor immune properties, and immunotherapy response of colon adenocarcinoma patients

“…11 Furthermore, data acquired from several solid tumors shows that tumor immunometabolic reprogramming is highly essential, which will continue to be a new emphasis of COAD research in the future. [12][13][14] Fatty acids are essential for energy storage, membrane synthesis, and signaling molecule production during oncogenesis. 15 It has been shown that decoding the molecular mechanism of COAD and fatty acid metabolism might aid in the identification of new therapeutic targets and the development of successful treatment techniques.…”

“…The disruption of lipid metabolism, specifically for fatty acid metabolism with altered expression and activity of lipid‐metabolizing enzymes as a result of abnormal activation of oncogenic signaling pathways, has been widely recognized as a critical factor of metabolic reconfiguration within cancer cells and immune cells that may lead to the long‐term development of COAD 11 . Furthermore, data acquired from several solid tumors shows that tumor immunometabolic reprogramming is highly essential, which will continue to be a new emphasis of COAD research in the future 12–14 . Fatty acids are essential for energy storage, membrane synthesis, and signaling molecule production during oncogenesis 15 .…”