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

• Published in: International journal of cancer 2011-05, Vol.128 (9), p.2085-2095
• Main Authors: Singer, Katrin, Kastenberger, Michael, Gottfried, Eva, Hammerschmied, Christine G., Büttner, Maike, Aigner, Michael, Seliger, Barbara, Walter, Bernhard, Schlösser, Hans, Hartmann, Arndt, Andreesen, Reinhard, Mackensen, Andreas, Kreutz, Marina
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Biological and medical sciences; Carcinoma, Renal Cell - immunology; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; CD3 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Clear cells; Data processing; Effector cells; Epithelium; Female; Foxp3 protein; Glucose metabolism; Glucose Transporter Type 1 - biosynthesis; glucose‐transporter 1; Glycolysis; granzyme B; Hepatocellular carcinoma; Humans; immune escape; Immunohistochemistry; Kidney; Kidney Neoplasms - immunology; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Kidneys; L-Lactate dehydrogenase; Lactic acid; LDHA; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Male; Medical sciences; Melanoma; Metastases; Middle Aged; mRNA; Neoplasm Staging; Nephrology. Urinary tract diseases; Oxygen; Perforin; Phenotype; renal cell carcinoma; RNA, Messenger - analysis; TIL; Tissue Array Analysis; Tumor cell lines; Tumor-infiltrating lymphocytes; Tumors; Tumors of the urinary system; Warburg; Young Adult
• ISSN: 0020-7136; 1097-0215; 1097-0215
• DOI: 10.1002/ijc.25543

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.