Mononuclear cell infiltration in clear‐cell renal cell carcinoma independently predicts patient survival

Webster, W. Scott; Lohse, Christine M.; Thompson, R. Houston; Dong, Haidong; Frigola, Xavier; Dicks, Demetrius; Sengupta, Shamik; Frank, Igor; Leibovich, Bradley C.; Blute, Michael L.; Cheville, John C.; Kwon, Eugene D.

doi:10.1002/cncr.21951

Cited by 73 publications

(64 citation statements)

References 31 publications

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“…In contrast, proximal tubules of the kidney, from which clear cell RCC tumors originate, were devoid of B7-H4 staining (22)(23)(24). Tumor B7-H4 expression was also associated with lymphocytic infiltration, which portends a poorer clinical outcome for patients with RCC (25). In addition, we observed that B7-H4 is associated with an increased risk of death from RCC and a higher risk for disease progression in patients with pathologically localized renal tumors in univariate analysis.…”

Section: Discussionmentioning

confidence: 99%

B7-H4 expression in renal cell carcinoma and tumor vasculature: Associations with cancer progression and survival

Krambeck¹,

Thompson²,

Dong³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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B7-H4 is a recently described B7 family coregulatory ligand that has been implicated as an inhibitor of T cell-mediated immunity. Although expression of B7-H4 is typically limited to lymphoid cells, aberrant B7-H4 expression has also been reported in several human malignancies. To date, associations of B7-H4 with clinical outcomes for cancer patients are lacking. Therefore, we examined B7-H4 expression in fresh-frozen tumor specimens from 259 renal cell carcinoma (RCC) patients treated with nephrectomy between 2000 and 2003 and performed correlative outcome analyses. We report that 153 (59.1%) RCC tumor specimens exhibited B7-H4 staining and that tumor cell B7-H4 expression was associated with adverse clinical and pathologic features, including constitutional symptoms, tumor necrosis, and advanced tumor size, stage, and grade. Patients with tumors expressing B7-H4 were also three times more likely to die from RCC compared with patients lacking B7-H4 (risk ratio ‫؍‬ 3.05; 95% confidence interval ‫؍‬ 1.51-6.14; P ‫؍‬ 0.002). Additionally, 211 (81.5%) specimens exhibited tumor vasculature endothelial B7-H4 expression, whereas only 6.5% of normal adjacent renal tissue vessels exhibited endothelial B7-H4 staining. Based on these findings, we conclude that B7-H4 has the potential to be a useful prognostic marker for patients with RCC. In addition, B7-H4 represents a target for attacking tumor cells as well as tumor neovasculature to facilitate immunotherapeutic treatment of RCC tumors. Last, we demonstrate that patients with RCC tumors expressing both B7-H4 and B7-H1 are at an even greater risk of death from RCC.B7-H1 ͉ costimulation ͉ tumor biomarker ͉ immunotherapy ͉ kidney neoplasms

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Section: Discussionmentioning

confidence: 99%

B7-H4 expression in renal cell carcinoma and tumor vasculature: Associations with cancer progression and survival

Krambeck¹,

Thompson²,

Dong³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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279

251

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“…However, a high infiltration rate of lymphocytes in RCC, particularly the clear cell type, is not correlated with a better clinical outcome, 28,29 whereas T cell infiltration is positively correlated with good prognosis in other tumors e.g., colon carcinoma. 26,27 This may indicate that tumor immune escape mechanisms may play an important role in RCC (reviewed in 31 ).…”

Section: Tumor Immunologymentioning

confidence: 95%

“…24,25 Therefore, in contrast to colon carcinoma and other solid tumors exhibiting a positive correlation between the numbers of tumor infiltrating lymphocytes and prognosis 26,27 no clear correlation was observed in RCC patients. 28,29 Furthermore, van den Hove and coauthors showed that tumor infiltrating CD8 þ T cells are highly activated, but functionally impaired. 30 These data indicate the presence of immune escape mechanisms in RCC that contribute to the failure of the immune system to control RCC growth (reviewed in 31 ).…”

mentioning

confidence: 99%

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

Singer

Kastenberger

Gottfried³

et al. 2011

Intl Journal of Cancer

137

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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...

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“…Several groups have reported that the presence of infiltrating mononuclear cells, including intratumor CD4 ϩ T cells, paradoxically, identifies patients with a poor prognosis (8,9). This observation suggests that a subset of tumor-infiltrating CD4 ϩ T cells may impede antitumor T and NK cell function (10).…”

Section: Targeting Molecular and Cellular Inhibitory Mechanisms For Imentioning

confidence: 99%

Targeting Molecular and Cellular Inhibitory Mechanisms for Improvement of Antitumor Memory Responses Reactivated by Tumor Cell Vaccine

Webster¹,

Thompson²,

Harris

et al. 2007

The Journal of Immunology

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Development of effective vaccination approaches to treat established tumors represents a focus of intensive research because such approaches offer the promise of enhancing immune system priming against tumor Ags via restimulation of pre-existing (memory) antitumoral helper and effector immune cells. However, inhibitory mechanisms, which function to limit the recall responses of tumor-specific immunity, remain poorly understood and interfere with therapies anticipated to induce protective immunity. The mouse renal cell carcinoma (RENCA) tumor model was used to investigate variables affecting vaccination outcomes. We demonstrate that although a whole cell irradiated tumor cell vaccine can trigger a functional antitumor memory response in the bone marrows of mice with established tumors, these responses do not culminate in the regression of established tumors. In addition, a CD103+ regulatory T (Treg) cell subset accumulates within the draining lymph nodes of tumor-bearing mice. We also show that B7-H1 (CD274, PD-L1), a negative costimulatory ligand, and CD4+ Treg cells collaborate to impair the recall responses of tumor-specific memory T cells. Specifically, mice bearing large established RENCA tumors were treated with tumor cell vaccination in combination with B7-H1 blockade and CD4+ T cell depletion (triple therapy treatment) and monitored for tumor growth and survival. Triple treatment therapy induced complete regression of large established RENCA tumors and raised long-lasting protective immunity. These results have implications for developing clinical antitumoral vaccination regimens in the setting in which tumors express elevated levels of B7-H1 in the presence of abundant Treg cells.

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Mononuclear cell infiltration in clear‐cell renal cell carcinoma independently predicts patient survival

Cited by 73 publications

References 31 publications

B7-H4 expression in renal cell carcinoma and tumor vasculature: Associations with cancer progression and survival

B7-H4 expression in renal cell carcinoma and tumor vasculature: Associations with cancer progression and survival

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

Targeting Molecular and Cellular Inhibitory Mechanisms for Improvement of Antitumor Memory Responses Reactivated by Tumor Cell Vaccine

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Mononuclear cell infiltration in clear‐cell renal cell carcinoma independently predicts patient survival

Cited by 73 publications

References 31 publications

B7-H4 expression in renal cell carcinoma and tumor vasculature: Associations with cancer progression and survival

B7-H4 expression in renal cell carcinoma and tumor vasculature: Associations with cancer progression and survival

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

Targeting Molecular and Cellular Inhibitory Mechanisms for Improvement of Antitumor Memory Responses Reactivated by Tumor Cell Vaccine

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