Immunotherapy for Renal Cell Carcinoma

Immunotherapy plays a significant role in the management of renal cell carcinoma (RCC) patients with metastatic disease because RCC is highly resistant to both chemotherapy and radiation therapy. Many reports illustrate various approaches to the treatment of RCC, such as cytokine-, antigen- or dendritic cell- (DC-) based immunotherapy, and the safety and effectiveness of immunotherapy have been highlighted by multiple clinical trials. Although antitumor immune responses and clinically significant outcomes have been achieved in these trials, the response rate is still low, and very few patients show long-term clinical improvement. Recently, the importance of immune regulation by antigen-presenting cells (APC) and regulatory T cells (Treg cells) has also been discussed. The authors outline the principles of cell-mediated tumor immunotherapy and discuss clinical trials of immunotherapy for RCC

Largen: A Molecular Regulator of Mammalian Cell Size Control

Little is known about how mammalian cells maintain cell size homeostasis. We conducted a novel genetic screen to identify cell-size-controlling genes and isolated Largen, the product of a gene (PRR16) that increased cell size upon overexpression in human cells. Invitro evidence indicated that Largen preferentially stimulates the translation of specific subsetsof mRNAs, including those encoding proteins affecting mitochondrial functions. The involvement of Largen in mitochondrial respiration was consistentwith the increased mitochondrial mass and greater ATP production in Largen-overexpressing cells. Furthermore, Largen overexpression led to increased cell size invivo, as revealed by analyses of conditional Largen transgenic mice. Our results establish Largen as an important link between mRNA translation, mitochondrial functions, and the control of mammalian cell size

Autophagy-independent functions of UVRAG are essential for peripheral naive T-cell homeostasis

UV radiation resistance-associated gene (UVRAG) encodes a tumor suppressor with putative roles in autophagy, endocytic trafficking, and DNA damage repair but its in vivo role in T cells is unknown. Because conditional homozygous deletion of Uvrag in mic

Glutathione Primes T Cell Metabolism for Inflammation

Activated T cells produce reactive oxygen species (ROS), which trigger the antioxidative glutathione (GSH) response necessary to buffer rising ROS and prevent cellular damage. We report that GSH is essential for T cell effector functions through its regulation of metabolic activity. Conditional gene targeting of the catalytic subunit of glutamate cysteine ligase (Gclc) blocked GSH production specifically in murine T cells. Gclc-deficient T cells initially underwent normal activation but could not meet their increased energy and biosynthetic requirements. GSH deficiency compromised the activation of mammalian target of rapamycin-1 (mTOR) and expression of NFAT and Myc transcription factors, abrogating the energy utilization and Myc-dependent metabolic reprogramming that allows activated T cells to switch to glycolysis and glutaminolysis. In vivo, T-cell-specific ablation of murine Gclc prevented autoimmune disease but blocked antiviral defense. The antioxidative GSH pathway thus plays an unexpected role in metabolic integration and reprogramming during inflammatory T cell responses.D.B. and K.H. are supported by the ATTRACT program and D.B. by a CORE grant (C15/BM/10355103) of the National Research Fund Luxembourg (FNR). V.V. holds a grant from the NIH NIAAA (5R24AA022057-05). This study was supported by the German Research Council (DFG, SFB974, LA-2558-5/1). M.L. and O.P. are funded by the Deutsches Zentrum fur Infektionsforschung and the University Hospital € Giessen Marburg. T.W.M. holds grants from the National Multiple Sclerosis Society (RG 5035-A-2) and the Canadian Institutes of Health Research (143268, MOP-123276)