Expression of RHAMM/CD168 and other tumor-associated antigens in patients with B-cell chronic lymphocytic leukemia

The receptor for hyaluronic acid-mediated motility (RHAMM) is a tumor-associated antigen in chronic lymphocytic leukemia (CLL). CD8 þ T cells primed with the RHAMM-derived epitope R3, which is restricted by human leukocyte antigen (HLA)-A2, effectively lyse RHAMM þ CLL cells. Therefore, we initiated a phase I clinical trial of R3 peptide vaccination. Six HLA-A2 þ CLL patients were vaccinated four times at biweekly intervals with the R3 peptide (ILSLELMKL; 300 lg per dose) emulsified in incomplete Freund's adjuvant; granulocyte-macrophage colony stimulating factor (100 lg per dose) was administered concomitantly. Detailed immunological analyses were conducted throughout the course of peptide vaccination. No severe adverse events greater than CTC I1 skin toxicity were observed. Four patients exhibited reduced white blood cell counts during vaccination. In five of six patients, R3-specific CD8 þ T cells were detected with the corresponding peptide/HLA-A2 tetrameric complex; these populations were verified functionally in four of five patients using enzyme-linked immunosorbent spot (ELISpot) assays. In patients with clinical responses, we found increased frequencies of R3-specific CD8 þ T cells that expressed high levels of CD107a and produced both interferon-c and granzyme B in response to antigen challenge. Interestingly, vaccination was also associated with the induction of regulatory T cells in four patients. Thus peptide vaccination in six CLL patients was safe and could elicit to some extent specific CD8 þ T-cell responses against the tumor antigen RHAMM.

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“…Mixed lymphocyte peptide culture (MLPC) was performed for influenza matrix peptide and R3 as previously described. 14 …”

Section: Mlpcmentioning

confidence: 99%

Peptide vaccination elicits leukemia-associated antigen-specific cytotoxic CD8+ T-cell responses in patients with chronic lymphocytic leukemia

et al. 2010

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“…13,14 On the basis of previous studies by others 15,16 and our own group, 13,14 we used the RHAMM-derived HLA-A2-restricted CD8 þ T-cell epitope R3 (position 165-173: ILSLELMKL), fibromodulin (FMOD)-derived (position 250-259: YMEHNN-VYTV) and survivin-derived (position 97-106: ELTLGEFLKL). This particular FMOD peptide sequence was chosen as it showed a superior immunogenicity when compared to the three other peptides described by Mayr et al 17 The influenza matrix protein (IMP)-derived peptide (GILGFVFTL) was used as a positive control, the melanoma antigen-derived peptide (FLWGPRALV) as an irrelevant peptide, that is, negative control.…”

Section: Mixed Lymphocyte Peptide Culturementioning

confidence: 99%

“…13 The PCR products were then separated by agarose gel electrophoresis and visualized with ethidium bromide using UV light.…”

Section: Hla-a2 Typingmentioning

confidence: 99%

Vaccination of B-CLL patients with autologous dendritic cells can change the frequency of leukemia antigen-specific CD8+ T cells as well as CD4+CD25+FoxP3+ regulatory T cells toward an antileukemia response

et al. 2008

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Recently, we described that vaccination with allogeneic dendritic cells (DCs) pulsed with tumor cell lysate generated specific CD8 þ T cell response in patients with B-cell chronic lymphocytic leukemia (B-CLL). In the present study, the potential of autologous DCs pulsed ex vivo with tumor cell lysates to stimulate antitumor immunity in patients with B-CLL in early stages was evaluated. Twelve patients at clinical stage 0-2 as per Rai were vaccinated intradermally up to eight times with a mean number of 7.4 Â 10 6 DCs pulsed with B-CLL cell lysate. We observed a decrease of peripheral blood leukocytes and CD19 þ /CD5 þ leukemic cells in five patients, three patients showed a stable disease and four patients progressed despite DC vaccination. A significant increase of specific cytotoxic CD8 þ T lymphocytes against the leukemia-associated antigens RHAMM or fibromodulin was detected in four patients after DC vaccination. In patients with a clinical response, an increase of interleukin 12 (IL-12) serum levels and a decrease of the frequency of CD4 þ CD25 þ FOXP3 þ T regulatory cells were observed. Taken together, the study demonstrated that vaccination with autologous DC in CLL patients is feasible and safe. Immunological and to some extend hematological responses could be noted, justifying further investigation on this immunotherapeutical approach.

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“…RHAMM is not only a modulator of growth factor receptor, but also has major roles in progression and proliferation of various types of cancer (9,11). RHAMM has been found in a variety of mammalian cells, including smooth muscle cells, endothelial cells, nerve cells, macrophages, spermatozoa (12,13), and certain types of tumor cell, including prostate (14), breast (15) and gastric (16) cancer, and B-cell chronic lymphocytic leukemia (17). However, whether the upregulation of RHAMM contributes to hepatocarcinogenesis of HCC remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of hyaluronan-mediated motility receptor in hepatocellular carcinoma predicts poor survival

Liao

Li³

et al. 2015

Oncology Letters

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Abstract. Hepatocellular carcinoma (HCC) is one of the most common types of cancer across the world. Hyaluronic acid (HA) has been reported to serve an important role in tumor extension, progression, migration and invasion. In addition, the receptor for HA-mediated motility (RHAMM) has been demonstrated to be overexpressed in different types of cancer. However, whether the upregulation of RHAMM contributes to hepatocarcinogenesis of HCC remains unclear. The present study examined the RHAMM expression in 187 HCC patients by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). RHAMM expression was significantly upregulated in liver cancer tissues compared with that observed in adjacent normal liver tissues. The IHC analysis demonstrated that RHAMM was overexpressed in 18 (72.0%) of the 25 HCC tissues. Furthermore, overexpression of RHAMM was associated with tumor-node-metastasis (TNM), the presence of vascular invasion and recurrence. Notably, the present study indicated that the overexpression of RHAMM was closely associated with the shorter disease-free and overall survival, so it may be a potential independent predictor for disease-free and overall survival of HCC patients. In conclusion, the upregulation of RHAMM is associated with HCC progression and prognosis; and it may be a potential independent predictor of disease-free and overall survival of HCC following surgical resection. IntroductionLiver cancer is one of the most common neoplasms worldwide, and hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer and accounts for 70-85% of all cases (1), ranking the sixth most common malignant tumors worldwide (2). More than 600,000 people lose their lives due to HCC every year (3), and HCC is the third most frequent cause of cancer-associated mortality (4). Previous studies have demonstrated that the incidence rate of HCC has been increasing. Surgical resection and liver-transplantation are superior therapeutic methods for HCC compared with other treatments, including radiofrequency ablation (RFA), transarterial chemoembolization (TACE) and chemotherapy, the treatment outcomes remain unsatisfactory owing to the high recurrence rate and high fatality rate of HCC (2). If HCC was detected and diagnosed earlier, surgical resection and liver-transplantation would result in an improved curative effect, therefore improving the disease-free and overall survival. The serum levels of α-fetoprotein (AFP) and ultrasonography (US) are widely used to screen for and assess HCC throughout the world. However, the sensitivity and specificity of AFP for HCC diagnosis and surveillance have certain limitations; US depends on the operator's skill, and clinicians are not always able to distinguish HCC clearly from other nodules (5). Consequently, novel potential serum biomarkers are required for prognosis and metastatic recurrence of HCC.Hyaluronic acid (HA) is an extracellular matrix (ECM) polymer and is frequently localized in the stroma of solid tumors, which is s...

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Expression of RHAMM/CD168 and other tumor-associated antigens in patients with B-cell chronic lymphocytic leukemia

Cited by 39 publications

References 38 publications

Peptide vaccination elicits leukemia-associated antigen-specific cytotoxic CD8+ T-cell responses in patients with chronic lymphocytic leukemia

Peptide vaccination elicits leukemia-associated antigen-specific cytotoxic CD8+ T-cell responses in patients with chronic lymphocytic leukemia

Vaccination of B-CLL patients with autologous dendritic cells can change the frequency of leukemia antigen-specific CD8+ T cells as well as CD4+CD25+FoxP3+ regulatory T cells toward an antileukemia response

Upregulation of hyaluronan-mediated motility receptor in hepatocellular carcinoma predicts poor survival

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