Warburg phenotype in renal cell carcinoma: high expression of glucose-transporter 1 (GLUT-1) correlates with low CD8(+) T-cell infiltration in the tumor.
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.
Singer
Katrin
K
Department of Internal Medicine 5, Haematology/Oncology, University of Erlangen, Erlangen, Germany.
Kastenberger
Michael
M
Gottfried
Eva
E
Hammerschmied
Christine G
CG
Büttner
Maike
M
Aigner
Michael
M
Seliger
Barbara
B
Walter
Bernhard
B
Schlösser
Hans
H
Hartmann
Arndt
A
Andreesen
Reinhard
R
Mackensen
Andreas
A
Kreutz
Marina
M
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
D051272:Glucose Transporter Type 1; D012333:RNA, Messenger