Journal Article

Identification of novel myeloma-specific XBP1 peptides able to generate cytotoxic T lymphocytes: a potential therapeutic application in multiple myeloma

Anderson, K C, Bae, J, Munshi, N C, Prabhala, R, Tai, Y-T, Carrasco, R, Lee, A-H

2011

Overview

The purpose of these studies was to identify human leukocyte antigen (HLA)-A2 + immunogenic peptides derived from XBP1 antigens to induce a multiple myeloma (MM)-specific immune response. Six native peptides from non-spliced XBP1 antigen and three native peptides from spliced XBP1 antigen were selected and evaluated for their HLA-A2 specificity. Among them, XBP1 184−192 , XBP1 SP 196−204 and XBP1 SP 367−375 peptides showed the highest level of binding affinity, but not stability to HLA-A2 molecules. Novel heteroclitic XBP1 peptides, Y ISPWILAV or Y LFPQLISV, demonstrated a significant improvement in HLA-A2 stability from their native XBP1 184−192 or XBP1 SP 367−375 peptide, respectively. Cytotoxic T lymphocytes generated by repeated stimulation of CD3 + T cells with each HLA-A2-specific heteroclitic peptide showed an increased percentage of CD8 + (cytotoxic) and CD69 + /CD45RO + (activated memory) T cells and a lower percentage of CD4 + (helper) and CD45RA + /CCR7 + (naïve) T cells, which were distinct from the control T cells. Functionally, the cytotoxic T lymphocytes (CTL) demonstrated MM-specific and HLA-A2-restricted proliferation, interferon-γ secretion and cytotoxic activity in response to MM cell lines and importantly, cytotoxicity against primary MM cells. These data demonstrate the distinct immunogenic characteristics of unique heteroclitic XBP1 peptides, which induce MM-specific CTLs and highlights their potential application for immunotherapy to treat the patients with MM or its pre-malignant condition.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/1619/554/1834/1269 / 631/92/555 / 692/699/67/1059/2325 / 692/699/67/1990/804 / Amino Acid Sequence / Antigens / Biological and medical sciences / Cancer / Cancer Research / Care and treatment / CCR7 protein / CD3 antigen / CD4 antigen / CD45RA antigen / CD69 antigen / CD8 antigen / Cell Line, Tumor / Cell Proliferation / Critical Care Medicine / Cytotoxicity / Disease / DNA-Binding Proteins - chemistry / DNA-Binding Proteins - metabolism / Endoplasmic reticulum / Enzyme-Linked Immunosorbent Assay / Health aspects / Hematologic and hematopoietic diseases / Hematology / Histocompatibility antigen HLA / Humans / Immune response / Immune system / Immunodeficiencies. Immunoglobulinopathies / Immunogenicity / Immunoglobulinopathies / Immunoglobulins / Immunological memory / Immunopathology / Immunotherapy / Intensive / Interferon / Internal Medicine / Kinases / Leukemia / Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis / Leukocytes / Lymphocytes / Lymphocytes T / Medical sciences / Medicine / Medicine & Public Health / Memory cells / Multiple myeloma / Multiple Myeloma - metabolism / Multiple Myeloma - therapy / Oncology / original-article / Patients / Peptide Fragments - immunology / Peptide Fragments - metabolism / Peptide Fragments - therapeutic use / Peptides / Physiological aspects / Plasma / Proteins / Regulatory Factor X Transcription Factors / Risk factors / Stability / T cells / T-Lymphocytes, Cytotoxic - cytology / T-Lymphocytes, Cytotoxic - immunology / Toxicity / Transcription factors / Transcription Factors - chemistry / Transcription Factors - metabolism / Tumor necrosis factor-TNF / Vaccines / X-Box Binding Protein 1 / γ-Interferon