Defective Major Histocompatibility Complex Class I Expression in a Sarcomatoid Renal Cell Carcinoma Cell Line

Jakobsen, Michael K.; Restifo, Nicholas P.; Cohen, Peter A.; Marincola, Francesco M.; Cheshire, L.Bryan; Linehan, W. Marston; Rosenberg, Steven A.; Alexander, Richard B.

doi:10.1097/00002371-199505000-00004

Cited by 16 publications

(8 citation statements)

References 24 publications

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“…Therefore, we are fully aware of the limitation in drawing a definitive conclusion concerning the frequency of specific defect(s) for a given RCC type before more tumor lesions and cell lines are investigated. The total HLA class I loss identified here in the sarcomatoid RCC subtype is in line with a previous study in which another sarcomatoid RCC cell line known as UOK123 was found to have lost total HLA class I expression; however, no information was given regarding its underlying mechanism [11]. Therefore, given the notorious clinical feature of sarcomatoid RCC, our study may have provided useful pilot data regarding the molecular defects in this subtype that lead to a total HLA class I loss.…”

Section: Discussionsupporting

confidence: 90%

Total HLA class I loss in a sarcomatoid renal carcinoma cell line caused by the coexistence of distinct mutations in the two encoding β2-microglobulin genes

Hsieh

Hsu

Chang

et al. 2008

Cancer Immunol Immunother

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In renal cell carcinoma (RCC), HLA class I downregulation has been found in about 40% of the lesions examined. Since only scanty information is available about the molecular basis of these defects, we have investigated the mechanism(s) underlying HLA class I antigen down-regulation or loss in six RCC cell lines. Five of them express HLA class I antigens although at various levels; on the other hand, HLA class I antigens are not detectable on the remaining cell line, the RCC52 cell line, belonging to a sarcomatoid subtype, even following incubation with IFN-γ. β 2 -microglobulin (β 2 m) was not detected in RCC52 cells. Surprisingly, RCC52 cells harbor two mutations in the β 2 m genes in exon 1: a single G deletion (delG) in codon 6, which introduces a premature stop at codon 7, and a CT dinucleotide deletion (delCT), which leads to a premature stop at codon 55. Analysis of eight clonal sublines isolated from the RCC52 cell line showed that the two β 2 m gene mutations are carried separately by RCC52 cell subpopulations. The delG/delCT double mutations were detected in two sublines with a fibroblast-like morphology, while the delCT mutation was detected in the remaining six sublines with an epithelial cell morphology. Furthermore, loss of heterozygosity (LOH) of the β 2 m gene at STR D15S-209 was found only in the epithelioid subpopulation, indicating loss of one copy of chromosome 15. Immunostaining results of the tumor lesion from which the cell line RCC52 was originated were consistent with the phenotyping/ molecular findings of the cultured cells. This is the first example of the coexistence of distinct β 2 m defects in two different tumor subpopulations of a RCC, where loss of one copy of chromosome 15 occurs in one of the subpopulations with total HLA class I antigen loss.

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Section: Discussionsupporting

confidence: 90%

Total HLA class I loss in a sarcomatoid renal carcinoma cell line caused by the coexistence of distinct mutations in the two encoding β2-microglobulin genes

Hsieh

Hsu

Chang

et al. 2008

Cancer Immunol Immunother

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“…Alternatively, tumour cells may have developed mechanisms that allow immune escape. Those mechanisms proposed include suppression mediated by cytokines released by tumour cells, 17 and reduced expression of MHC and costimulatory molecules on tumour cells 18 , 19 . More recent evidence suggests that expression of the apoptotic death factor molecule, Fas (APO‐1/CD95) ligand (Fas L), on tumour cells may represent a novel mechanism of immune evasion 20 , 21 , 22 , 23 , 24 .…”

Section: Introductionmentioning

confidence: 99%

Expression of apoptotic regulatory molecules in renal cell carcinoma: Elevated expression of Fas ligand

Olive¹,

Cheung²,

Nicol

et al. 1999

Immunol Cell Biol

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Renal cell carcinoma (RCC) is the most common renal neoplasm. Despite being infiltrated by tumour infiltrating lymphocytes (TIL), these TIL are unable to control tumour growth in vivo, suggesting that the cytotoxic capacity of TIL against RCC is impaired, or that the tumour cells are resistant to killing and therefore escape detection by the immune system. It is postulated that the expression of apoptotic regulatory molecules in RCC favours tumour cell survival. The present study has therefore determined the expression of Fas (APO‐1/CD95), Fas ligand (Fas L) and bcl‐2 in these tumours. The expression of Fas, Fas L and bcl‐2 mRNA transcripts was determined in RCC, normal kidney and peripheral blood by semiquantitative reverse transcriptase polymerase chain reaction (RT‐PCR), following RNA extraction and cDNA synthesis from tissues and cell samples. Transcript levels were measured by densitometry after Southern blot hybridization of PCR products with internal radio‐labelled oligonucleotide probes; a densitometry score was assigned to each hybridizing DNA band and expressed as a ratio of the glyceraldehyde‐3‐phosphate dehydrogenase content. In peripheral blood, the expression of Fas L and bcl‐2 transcripts was similar between patients and normal healthy individuals; however, Fas transcript expression was significantly down‐regulated in the patients’ versus normal peripheral blood (P = 0.026). Most interestingly, significantly up‐regulated Fas L expression was observed in RCC compared to normal kidney (P = 0.041). In contrast, bcl‐2 transcripts were well represented in normal kidney but markedly decreased in RCC (P = 0.021). The expression of Fas transcripts in normal kidney and RCC was variable. These data demonstrate elevated expression of Fas L transcripts in RCC, but the functional relevance of this remains to be investigated.

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“…In an assessment of 12 RCC patient-derived cell lines, Jakobsen et al identified a lack of both β 2 -microglobulin expression and major histocompatibility complex (MHC) class I expression in a cell line derived from a patient with sarcomatoid disease. [16] Notably, β 2 -microglobulin allows for appropriate folding of MHC class I complex on the cell surface – the lack of this complex precludes antigen presentation and allows for immune invasion. In a separate effort, Kuriowa et al performed a detailed immunohistochemical analysis of 12 specimens derived from patients with sarcomatoid RCC.…”

Section: Discussionmentioning

confidence: 99%

Clinical outcome in patients receiving systemic therapy for metastatic sarcomatoid renal cell carcinoma: A retrospective analysis☆

Pal¹,

Jones²,

Carmichael³

et al. 2013

Urologic Oncology: Seminars and Original Investigations

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OBJECTIVES Sarcomatoid metastatic renal cell carcinoma (mRCC) represents an aggressive subset of disease, and a definitive therapeutic strategy is lacking. We seek to define outcomes associated with systemic therapy (including immunotherapy, cytotoxic therapy, and targeted agents) for sarcomatoid mRCC, with attention to novel prognostic schema. MATERIALS AND METHODS From an institutional database including 270 patients with mRCC, we identified 34 patients with documented sarcomatoid features. Within this cohort, we assessed 21 patients who received systemic therapy. Survival was assessed in the overall cohort and in subgroups divided by clinicopathologic characteristics, including the extent of sarcomatoid features, Memorial Sloan-Kettering Cancer Center (MSKCC) risk criteria, Heng criteria, and the nature of systemic therapy rendered. RESULTS Of the 21 patients assessed, 2 patients received chemotherapy, 7 patients received immunotherapy, and 12 patients received targeted agents as their first line treatment. Median overall survival (OS) in the overall cohort was 18.0 months (95%CI 6.9–22.0). By MSKCC criteria, patients with poor-risk disease had a median OS of 4.7 months, as compared to 20.1 months for patients with intermediate-risk disease (hazard ratio, HR, 0.02, 95%CI 0.003–0.15; P=0.0001). A similar difference in median OS was seen poor- and intermediate-risk groups when stratifying by Heng criteria (HR 0.17, 95%CI 0.001–0.12). There was no significant difference in survival in patients with sarcomatoid predominant disease vs non-predominant disease (HR 0.62, 95%CI 0.23–1.65; P=0.34), nor was there a difference amongst patients who received targeted therapies vs non-targeted therapies (HR 1.0, 95%CI 0.61–1.40; P=0.36). CONCLUSIONS As compared to previous series and prospective trials assessing patients with sarcomatoid mRCC, the observed survival was prolonged. Although both Heng and MSKCC risk scores may be useful in determining prognosis, further studies are needed to identify relevant biomarkers and define the optimal therapeutic strategy for this disease.

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Defective Major Histocompatibility Complex Class I Expression in a Sarcomatoid Renal Cell Carcinoma Cell Line

Cited by 16 publications

References 24 publications

Total HLA class I loss in a sarcomatoid renal carcinoma cell line caused by the coexistence of distinct mutations in the two encoding β2-microglobulin genes

Total HLA class I loss in a sarcomatoid renal carcinoma cell line caused by the coexistence of distinct mutations in the two encoding β2-microglobulin genes

Expression of apoptotic regulatory molecules in renal cell carcinoma: Elevated expression of Fas ligand

Clinical outcome in patients receiving systemic therapy for metastatic sarcomatoid renal cell carcinoma: A retrospective analysis☆

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