Warburg phenotype in renal cell carcinoma: high expression of glucose-transporter 1 (GLUT-1) correlates with low CD8+ T-cell infiltration in the tumor
Warburg phenotype in renal cell carcinoma: high expression of glucose-transporter 1 (GLUT-1) correlates with low CD8+ T-cell infiltration in the tumor
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DOI：
10.1002/ijc.25543
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发表时间：
2011-05-01
影响因子：
6.4
通讯作者：
Kreutz, Marina
中科院分区：
文献类型：
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作者：
Singer, Katrin;Kastenberger, Michael;Kreutz, Marina
许多肿瘤细胞的特征是糖代谢失调，在氧气存在下糖酵解增加（“Warburg效应”）。在这里，我们首次分析了肾细胞癌（RCC）中葡萄糖代谢与免疫细胞浸润之间的可能联系。与正常肾组织相比，RCC标本中乳酸脱氢酶a （LDHA）和葡萄糖转运蛋白1 （GLUT-1）的mRNA水平显著升高。因此，不同来源的肿瘤细胞系，如RCC、黑色素瘤和肝细胞癌，与非恶性肿瘤细胞系相比，强烈表达LDHA和GLUT-1。与这一发现一致，肿瘤细胞分泌大量乳酸。249例RCC标本的组织芯片分析证实了GLUT-1和LDH5 （LDH5是4个LDHA亚基的四聚体）的高表达。总体而言，55/79（69.6%）和46/71（64.7%）的透明细胞癌分别表现出组成性但异质性的GLUT-1和LDH5表达。与正常肾上皮细胞相比，RCC病变中CD3（+）、CD8（+）和FOXP3(+) T细胞数量显著升高，但肿瘤浸润T细胞中颗粒酶B和穿孔素等效应分子减少。有趣的是，进一步的分析显示，在RCC病变中，GLUT-1表达与CD8(+) T细胞数量呈负相关。总之，我们的数据表明，RCC组织中葡萄糖代谢的加速与CD8（+）效应T细胞的低浸润有关。靶向葡萄糖代谢可能是一种有趣的工具，可以提高RCC特异性免疫治疗方法的疗效。
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.