The tumor antigens RHAMM and G250/CAIX are expressed in head and neck squamous cell carcinomas and elicit specific CD8+ T cell responses

Schmitt, Anita; Barth, Thomas F.E.; Beyer, Eva; Borchert, Franziska; Rojewski, Markus; Chen, Jinfei; Guillaume, Philippe; Gronau, Silke; Greiner, Jochen; Möller, Peter; Riechelmann, Herbert; Schmitt, Michael

doi:10.3892/ijo_00000188

Cited by 29 publications

(27 citation statements)

References 35 publications

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“…29 Hydroxylation of either human HIF-1α Pro 402 or Pro 564 promotes the interaction with pVHL, leading to the recruitment of ubiquitin complexes and degradation of HIF-1α. 12 FIH-1 was initially identified as a protein binding to HIF-1α and VHL and regulating the transcriptional activity of HIF-1. 24 Lando et al 30 showed that FIH-1 is an asparaginyl hydroxylase that regulates the transcriptional activity of HIF-1 by hydroxylating Asn 803 .…”

Section: Nicd3 Mutant Defective In Putative Vhl Binding Represses Thementioning

confidence: 99%

“…7 These antitumor mechanisms are not exploited by the classic cancer drugs and therefore represent a new anticancer drug discovery strategy. Overexpression of CA9 is consistently seen in a high proportion of carcinomas of the cervix, 8 clear cell carcinoma of the kidney, 9 and to a lesser extent in breast cancer, 10,11 carcinoma of the head and neck, 12,13 lung cancer, 14 and tumors of the brain. 15,16 Elevated expression of CA9 during hypoxia is suggestive of its importance during tumor adaptation to hypoxia.…”

Section: Introductionmentioning

confidence: 99%

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Interaction of HIF-1 and Notch3 Is Required for the Expression of Carbonic Anhydrase 9 in Breast Carcinoma Cells

et al. 2013

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Expression of carbonic anhydrase 9 (CA9) is associated with poor prognosis and increased tumor aggressiveness and does not always correlate with HIF-1α expression. Presently, we analyzed the regulation of CA9 expression during hypoxia by HIF-1α, Notch3, and the von Hippel-Lindau (VHL) in breast carcinoma cells. Both HIF-1α and Notch3 were absolutely required for the expression of CA9 mRNA, protein, and reporter. Reciprocal coimmunoprecipitation of HIF-1α, Notch3 intracellular domain (NICD3), and pVHL demonstrated their association. The presence of common consensus prolyl hydroxylation and pVHL binding motifs (L(XY)LAP);LLPLAP 2191 suggested an oxygen-dependent regulation for NICD3. However, unlike the HIF-1α protein, NICD3 protein levels were not modulated with hypoxia or hypoxia-mimetic agents. Surprisingly, mutations of the common prolyl hydroxylation and pVHL binding domain lead to the loss of CA9 mRNA, protein, and reporter activity. Chromatin immunoprecipitation assay demonstrated the association of NICD3, HIF-1α, and pVHL at the CA9 promoter. Further, the NICD3 mutant defective in prolyl hydroxylation and subsequent pVHL binding caused a reduction in cell proliferation of breast carcinoma cells. We show here for the first time that the interaction of HIF-1α with NICD3 is important for the regulation of CA9 expression. These findings suggest that although CA9 is a hypoxia-responsive gene, its expression is modulated by the interaction of HIF-1α, Notch3, and VHL proteins. Targeting the expression of CA9 by targeting upstream regulators could be useful in cancer/stem cell therapy.

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Section: Nicd3 Mutant Defective In Putative Vhl Binding Represses Thementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interaction of HIF-1 and Notch3 Is Required for the Expression of Carbonic Anhydrase 9 in Breast Carcinoma Cells

et al. 2013

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“…Therefore, a phase I vaccination trial was initiated in which patients developed specific CTL response after 4 vaccinations (22). Similar results were obtained in patients with chronic lymphocytic leukemia and tumors of the head/neck region (35).…”

Section: Discussionmentioning

confidence: 64%

Frequent T cell responses against immunogenic targets in lung cancer patients for targeted immunotherapy

et al. 2013

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Abstract. To date, lung cancer is one of the leading causes of cancer mortality with short overall survival despite adequate therapy. New immunotherapeutic strategies using peptides derived from tumor-associated antigens (TAAs) can induce a specific cytotoxic T cell (CTL) response leading to a targeted tumor cell death. In the present study, we addressed whether there are further significant immunogenic candidate targets that may induce strong immune reactions with a high frequency in lung cancer patients eligible for cellular immunotherapeutic approaches, such as in a polyvalent vaccination approach. In this study, we investigated specific CTL responses of 14 HLA-A * 0201-positive patients (of 33 screened patients) with non-small cell lung cancer (NSCLC; n=12) or small cell lung cancer (SCLC; n=2) against several known and novel TAA-derived peptides from lung cancer and/or other tumor entities, by measuring granzyme B (GrB) and/ or interferon γ (IFNγ) secretion using enzyme-linked immunospot (ELISpot) analysis. Specific T cell responses could be detected for hTERT (4/13), two MAGE-A3-derived peptides (4/13 and 3/13, respectively), RHAMM (4/14), PRAME (8/14), G250 (7/12), survivin (3/13), HER2 (5/10) and WT1 (2/14), but also novel epitopes derived from Aurora kinase A (4/13) and B (5/13). Additionally, simultaneous CTL responses against the different peptides were examined and specific T cell responses against at least one of these TAAs could be detected in 13/14 (93%) patients. It could be shown that all patients with immune reactions against RHAMM and hTERT showed also immune responses against PRAME. Furthermore, patients with CTL responses against the Aurora kinase A peptide (Aura A1) also demonstrated a response against the Aurora kinase B peptide (Aura B1). Taken together, we showed that these TAA-derived peptides induce frequent specific T cell responses in patients with metastatic lung cancer and are, therefore, novel candidates for targeted immunotherapies and polyvalent approaches.

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“…A previous CD168 knockdown study demonstrated growth reduction of transplanted tumors (28). Increased CD168 expression was revealed to be indicative of an elevated, or abnormal, level of cell proliferation in human OSCC (17).…”

Section: Discussionmentioning

confidence: 80%

“…), and is essential in cell migration and proliferation during embryogenesis (12). CD168 has been extensively studied in different tumor cell lines and a variety of tumor types, including lymphoid and myeloid malignancies, and colorectal, breast, ovarian and urothelial carcinoma (13)(14)(15)(16), although only a few studies have dealt with its expression and significance in the head-and-neck SCCs (17)(18)(19). It has been demonstrated that CD168 is required to facilitate proliferation of head-and-neck cancer cells (18).…”

Section: Introductionmentioning

confidence: 99%

Expression patterns of CD168 correlate with the stage and grade of squamous cell carcinoma of head and neck

Jöhrens

Anagnostopoulos

Dommerich

et al. 2017

Molecular and Clinical Oncology

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Abstract. The receptor for hyaluronan-mediated motility CD168 is associated with the processes of oncogenesis and metastasis. The objective of the present study was to determine the possible association between the expression and distribution of CD168 and the tumor stage of head-and-neck squamous cell carcinoma (SCC). Formalin-fixed and paraffinembedded tumor samples obtained from 100 patients during primary resection of SCC from the oral cavity, oropharynx, hypopharynx or larynx were included in the present study. The patients were divided into two risk groups: Low risk, representing the early stage of completely resected SCCs with good-to-moderate differentiation, and the high-risk group, representing the advanced stage SCCs with positive resection margins, vascular invasion or locoregional metastasis. All specimens were stained with a monoclonal antibody against CD168. Percentage and staining intensity of CD168-positive cells were scored, and their spatial distribution within the tumor nests was noted. The results obtained were correlated with the tumor stage. The quantification of CD168 expression revealed significant differences between the two risk groups (t-test, P=0.002), with higher scores in tumors resected from the highrisk SSC group compared with those from the low-risk group. In addition, in the high-risk group, the CD168-positive cells were present predominantly in the periphery (70.4%) of tumor nests, whereas in the low-risk group, only 56.6% were located there; however, this trend did not reach the level of statistical significance. Taken together, the results from the present study suggested that CD168 expression patterns could potentially be used as a predictor of tumor aggressiveness, and therefore they may be a prognostic factor in head-and-neck SCC.

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The tumor antigens RHAMM and G250/CAIX are expressed in head and neck squamous cell carcinomas and elicit specific CD8+ T cell responses

Cited by 29 publications

References 35 publications

Interaction of HIF-1 and Notch3 Is Required for the Expression of Carbonic Anhydrase 9 in Breast Carcinoma Cells

Interaction of HIF-1 and Notch3 Is Required for the Expression of Carbonic Anhydrase 9 in Breast Carcinoma Cells

Frequent T cell responses against immunogenic targets in lung cancer patients for targeted immunotherapy

Expression patterns of CD168 correlate with the stage and grade of squamous cell carcinoma of head and neck

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