Warburg phenotype in renal cell carcinoma: High expression of glucose‐transporter 1 (GLUT‐1) correlates with low CD8⁺ T‐cell infiltration in the tumor

Abstract

Many tumor cells are characterized by a dysregulated glucose metabolism associated with increased glycolysis in the presence of oxygen (''Warburg Effect''). Here, we analyzed for the first time a possible link between glucose metabolism and immune cell infiltration in renal cell carcinoma (RCC). RCC specimens revealed a highly significant increase in the expression of lactate dehydrogenase A (LDHA) and glucose-transporter 1 (GLUT-1) compared to the corresponding normal kidney tissue on mRNA level. Accordingly, tumor cell lines of different origin such as RCC, melanoma and hepatocellular carcinoma strongly expressed LDHA and GLUT-1 compared to their nonmalignant counterparts. In line with this finding, tumor cells secreted high amounts of lactate. High expression of GLUT-1 and LDH5, a tetramer of 4 LDHA subunits, was confirmed by tissue microarray analysis of 249 RCC specimens. Overall, 55/79 (69.6%) and 46/71 (64.7%) cases of clear cell carcinoma showed a constitutive, but heterogeneous expression of GLUT-1 and LDH5, respectively. The number of CD3 1 , CD8 1 and FOXP3 1 T cells was significantly elevated in RCC lesions compared to normal kidney epithelium, but effector molecules such as granzyme B and perforin were decreased in tumor infiltrating T cells. Of interest, further analysis revealed an inverse correlation between GLUT-1 expression and the number of CD8 1 T cells in RCC lesions. Together, our data suggest that an accelerated glucose metabolism in RCC tissue is associated with a low infiltration of CD8 1 effector T cells. Targeting the glucose metabolism may represent an interesting tool to improve the efficacy of specific immunotherapeutic approaches in RCC.Renal cell carcinoma (RCC) constitutes 2-3% of all malignant tumors in adults. It is a very heterogeneous malignancy, which is subdivided in different histological subtypes. The most common type of RCC is clear cell carcinoma with an incidence of 75% whereas the papillary (10-15%) and the chromophobe subtypes (5%) are less frequent. 1,2 Clear cell carcinoma arises from cells of the proximal tubule and is characterized by a clear cytoplasm, which stores glycogen. It is associated with a large number of gene mutations most notably in the von Hippel Lindau (VHL) gene. 3,4 The VHL protein is crucially involved in the regulation of the hypoxia inducible transcription factor HIF1. In the absence of VHL, HIF is stabilized and induces the expression of proteins that are involved in angiogenesis and glucose metabolism, e.g., vascular endothelial growth factor (VEGF), erythropoietin and glucose-transporter 1 (GLUT-1). 5,6 Overexpression of GLUT-1 has been described in different malignancies 7-9 and polymorphisms of GLUT-1 seems to be associated with clear cell carcinoma. 10 Beside HIF stabilization through loss of the tumor suppressor gene VHL or hypoxia, oncogenic transformation, caused by loss of p53, 11,12 mutation of KRAS/BRAF 13 or c-myc overexpression 14 reduces respiration accompanied by an upregulation of glycolytic enzymes such as lactate dehydrogena...

Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells

“…6,7 We and others have demonstrated, that lactic acid, a prominent product of glycolysis generated in increased amounts by tumor cells, is capable of modulating cellular components within the tumor stroma, including immune effector cells and antigen-presenting cells. [8][9][10][11] There is an increasingly recognized list of metabolic dysregulations linked to carcinogenesis. Various tumor entities, particularly malignant melanoma, leukemia, and hepatocellular carcinoma, can exhibit a reduced expression of 5 0 -deoxy-5 0 -methylthioadenosine phosphorylase (MTAP).…”

A laktátdehidrogenáz (LDH) prognosztikai jelentősége az onkológiában

“…Világossejtes veserák (RCC) biopsziás mintáinak vizsgálata során a GLUT-1-expresszió upregulációja negatív korrelációt mutatott a CD3+, CD8+ és granzyme B+ T-sejtek jelenlétével. Továbbá az LdhA génexpressziója negatív hatást gyakorol a CD3+ T-sejtek által végbemenő daganatos szöveti infiltrációra [51]. In vitro vizsgálatok alapján a tejsav gá-tolja a T-sejtek tejsavleadását [48].…”

The VHL-HIF Signaling in Renal Cell Carcinoma: Promises and Pitfalls

“…In order to counteract the deleterious effects of hypoxia, such as apoptosis and necrosis, malignant cells undergo adaptive and genetic changes. One such change is increased uptake of glucose when compared with normal cells through accelerated glycolysis -often referred to as 'glycolytic switch' or 'Warburg effect' (Warburg, 1956;Airley&Mobasheri, 2007;Singer et al, 2011). This is largely mediated by the up-regulation of GLUT especially GLUT-1 (Binder et al, 1997;Smith, 1999;Medina&Owen, 2002;Airley&Mobasheri, 2007;Ozcan et al, 2007;Suganuma et al, 2007).…”

“…This is largely mediated by the up-regulation of GLUT especially GLUT-1 (Binder et al, 1997;Smith, 1999;Medina&Owen, 2002;Airley&Mobasheri, 2007;Ozcan et al, 2007;Suganuma et al, 2007). It is now well established that accelerated glycolysis and increased glucose uptake mediated by GLUT-1 are the hallmarks of many malignant tumors and that these adaptive changes in glucose metabolism favor survival, proliferation and metastasis of tumor cells, even under hypoxic conditions (Airley&Mobasheri, 2007;Ozcan et al, 2007;Singer et al, 2011).…”

“…GLUT-1 is overexpressed in VHL-mutated mice and the GLUT-1 promoter region has an HRE (Ebert et al, 1995;Park et al, 2007;Lidgren et al, 2008). While the basal level of expression of GLUT-1 in normal PTEC is a subject of debate (Nagase et al, 1995;Ozcan et al, 2007), the overexpression of GLUT-1 in RCC has been demonstrated by many studies (Nagase et al, 1995;Miyakita et al, 2002;Ozcan et al, 2007;Suganuma et al, 2007;Lidgren et al, 2008;Singer et al, 2011). All of these studies concluded that GLUT-1 is over-expressed markedly in clear cell RCC compared with other RCC subtypes, confirming the link between VHL aberration and the subsequent HIF up-regulation.…”