Immune Responses to RHAMM in Patients with Acute Myeloid Leukemia after Chemotherapy and Allogeneic Stem Cell Transplantation

Abstract

Leukemic blasts overexpress immunogenic antigens, so-called leukemia-associated antigens like the receptor for hyaluronan acid-mediated motility (RHAMM). Persistent RHAMM expression and decreasing CD8+ T-cell responses to RHAMM in the framework of allogeneic stem cell transplantation or chemotherapy alone might indicate the immune escape of leukemia cells. In the present study, we analyzed the expression of RHAMM in 48 patients suffering from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Furthermore, we correlated transcripts with the clinical course of the disease before and after treatment. Real-time quantitative reverse transcriptase polymerase chain reaction was performed from RNA of peripheral blood mononuclear cells. T cell responses against RHAMM were assessed by tetramer staining (flow cytometry) and enzyme-linked immunospot (ELISPOT) assays. Results were correlated with the clinical outcome of patients. The results of the present study showed that almost 60% of the patients were RHAMM positive; specific T-cells recognizing RHAMM could be detected, but they were nonfunctional in terms of interferon gamma or granzyme B release as demonstrated by ELISPOT assays. Immunotherapies like peptide vaccination or adoptive transfer of RHAMM-specific T cells might improve the immune response and the outcome of AML/MDS patients.

Immune responses to WT1 in patients with AML or MDS after chemotherapy and allogeneic stem cell transplantation

“…MLPC was performed as described elsewhere . Briefly, specific CD8+ T cells were positively selected by magnetic‐activated cell sorting (MACS) columns (MiltenyiBiotec, Bergisch‐Gladbach, Germany).…”

“…The frequency of WT1‐specific T cells was determined by flow cytometry. Tetramer staining was performed as described previously . Briefly, lymphocytes were stained with WT1‐specific tetramers and posterior with conjugated antibodies to CD3 and CD8 (BD Biosciences).…”

The Roles of Hyaluronan/RHAMM/CD44 and Their Respective Interactions along the Insidious Pathways of Fibrosarcoma Progression

“…Thus, TCR-transgenic lymphocytes specific for RHAMM limit tumor outgrowth in vivo in various solid and leukemia tumor models [137]. It has been suggested that immunotherapies like peptide vaccination or adoptive transfer of RHAMM-specific T cells might improve the immune response and the outcome of acute myeloid leukemia patients [138]. Moreover, it has been shown in vivo that sulfated hyaluronan augmented tumor growth due to a blockade in complex formation between phosphoinositide 3-kinase (PI3K) and hyaluronan receptors and to a transcriptional downregulation of HA receptors, CD44, and RHAMM, along with PI3K inhibition [139].…”

Leukemic progenitor cells are susceptible to targeting by stimulated cytotoxic T cells against immunogenic leukemia‐associated antigens

“…Beside expression levels, presentation on MHC molecules and strong stimulation of T cells against the antigen is mandatory. RHAMM induces specific T cell responses in different malignancies including AML . In peptide vaccination trials, the induction of a high frequency of specific T cell responses could be detected and also positive clinical results but no relevant clinical toxicity was detected after peptide vaccination against RHAMM .…”

“…RHAMM induces specific T cell responses in different malignancies including AML. 17,31,42 In peptide vaccination trials, the induction of a high frequency of specific T cell responses could be detected and also positive clinical results but no relevant clinical toxicity was detected after peptide vaccination against RHAMM. 21,27,31 We further analyzed .…”