title: 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(+), CD8(+) and FOXP3(+) 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(+) 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(+) effector T cells. Targeting the glucose metabolism may represent an interesting tool to improve the efficacy of specific immunotherapeutic approaches in RCC.
authors.affiliation: Department of Internal Medicine 5, Haematology/Oncology, University of Erlangen, Erlangen, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Singer
authors.forename: Michael
authors.initials: M
authors.lastname: Kastenberger
authors.forename: Eva
authors.initials: E
authors.lastname: Gottfried
authors.forename: Christine G
authors.initials: CG
authors.lastname: Hammerschmied
authors.forename: Maike
authors.initials: M
authors.lastname: Büttner
authors.forename: Michael
authors.initials: M
authors.lastname: Aigner
authors.forename: Barbara
authors.initials: B
authors.lastname: Seliger
authors.forename: Bernhard
authors.initials: B
authors.lastname: Walter
authors.forename: Hans
authors.initials: H
authors.lastname: Schlösser
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Reinhard
authors.initials: R
authors.lastname: Andreesen
authors.forename: Andreas
authors.initials: A
authors.lastname: Mackensen
authors.forename: Marina
authors.initials: M
authors.lastname: Kreutz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D046888:Tissue Array Analysis; D055815:Young Adult
chemical_list: D051272:Glucose Transporter Type 1; D012333:RNA, Messenger