@article{98bbfc5a6bd04877bfd0dabdab3de89a,
title = "Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma",
abstract = "Cancer cells can inhibit effector T cells (Teff) through both immunomodulatory receptors and the impact of cancer metabolism on the tumor microenvironment. Indeed, Teff require high rates of glucose metabolism, and consumption of essential nutrients or generation of waste products by tumor cells may impede essential T cell metabolic pathways. Clear cell renal cell carcinoma (ccRCC) is characterized by loss of the tumor suppressor von Hippel-Lindau (VHL) and altered cancer cell metabolism. Here, we assessed how ccRCC influences the metabolism and activation of primary patient ccRCC tumor infiltrating lymphocytes (TIL). CD8 TIL were abundant in ccRCC, but they were phenotypically distinct and both functionally and metabolically impaired. ccRCC CD8 TIL were unable to efficiently uptake glucose or perform glycolysis and had small, fragmented mitochondria that were hyperpolarized and generated large amounts of ROS. Elevated ROS was associated with downregulated mitochondrial SOD2. CD8 T cells with hyperpolarized mitochondria were also visible in the blood of ccRCC patients. Importantly, provision of pyruvate to bypass glycolytic defects or scavengers to neutralize mitochondrial ROS could partially restore TIL activation. Thus, strategies to improve metabolic function of ccRCC CD8 TIL may promote the immune response to ccRCC.",
author = "Siska, {Peter J.} and Beckermann, {Kathryn E.} and Mason, {Frank M.} and Gabriela Andrejeva and Greenplate, {Allison R.} and Sendor, {Adam B.} and Chiang, {Yun Chen J.} and Corona, {Armando L.} and Gemta, {Lelisa F.} and Vincent, {Benjamin G.} and Wang, {Richard C.} and Bumki Kim and Jiyong Hong and Chen, {Chiu Lan} and Bullock, {Timothy N.} and Irish, {Jonathan M.} and Rathmell, {W. Kimryn} and Rathmell, {Jeffrey C.}",
note = "Funding Information: We thank the patients who participated by donating their tissue for this research and the Cooperative Human Tissue Network Western Division for RCC sample preparation. We also thank the members of WKR and JCR laboratories for support and helpful discussions. This work was supported by the For-beck Foundation (WKR, BGV), the Cancer Research Institute (JCR, KEB), Brock Fellowship Endowment (KEB), Vanderbilt-Incyte Alliance (JCR, WKR), the German Research Foundation (PJS; DFG KFO 262), and National Cancer Institute K24 CA172355 (WKR). Electron and confocal microscopy was performed in part through the use of the Vanderbilt Cell Imaging Shared Resource (supported by NIH grants CA68485, DK20593, DK58404, DK59637 and EY08126). Publisher Copyright: {\textcopyright} 2017 American Society for Clinical Investigation. All rights reserved.",
year = "2017",
month = jun,
day = "15",
doi = "10.1172/jci.insight.93411",
language = "English (US)",
volume = "2",
journal = "JCI insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "12",
}