Recognition of BCR-ABL positive leukemic blasts by human CD4+ T cells elicited by primary in vitro immunization with a BCR-ABL breakpoint peptide

Abstract

In chronic myeloid leukemia (CML) the classical 9;22 translocation results in a BCR-ABL fusion gene, which encodes chimeric BCR-ABL fusion 210 kD oncoproteins (p210BCR-ABL). The two main p210BCR-ABL fusion variants in CML, b2a2 and b3a2 are examples of well characterized antigens expressed by malignant cells. The possibility of an immunotherapeutic approach involving the fusion part of p210BCR-ABL in CML has previously been illustrated by observed peptide binding to major histocompatibility complex (MHC) class I alleles and by demonstrating the immunogenicity of p210BCR-ABL breakpoint peptides. In this report we show that in vitro immunization of human T cells with a 17 amino acid (aa) peptide representing the p210BCR-ABL fusion region resulted in peptide specific CD4+ T-cell lines designated P4, P6, and P7. HLA DR4 (DRB1*0401) restricted T-cell line P4 and several subsequently derived clones recognized HLA-DRB1*0401 and p210b3a2-mRNA expressing blasts from an allogeneic patient with CML in blast crisis. Recognition appeared DR expression-dependent. No responses were observed with DR4 positive p210BCR-ABL negative cells or with p210b3a2 leukemic cells with absent or insufficient expression of DR4. These observations indicate that oncoprotein p210b3a2 can be degraded and processed for presentation by MHC class II molecules at the surface of leukemic cells. The BCR-ABL fusion region is in all likelihood presented as peptides by HLA DR and thus capable to act as a distinctive tumor antigen to peptide specific CD4+ T cells.

A MAGE-1 peptide recognized on HLA-DR15 by CD4+ T cells

“…The peptide described here belongs to the category of tumor-specific antigens encoded by "cancer germline" genes, such as MAGE-3 and NY-ESO-1 LAGE-2 [24][25][26][27][28]. Other tumorspecific antigens recognized by CD4 + T cells are the result of point mutations in ubiquitously expressed genes, while others are fusion gene products [29][30][31][32][33]. A number of antigenic peptides presented by HLA class II molecules on melanoma derive from melanocyte differentiation proteins [34][35][36][37].…”

The impact of BCR‐ABL1 transcript type on tyrosine kinase inhibitor responses and outcomes in patients with chronic myeloid leukemia

“…It previously has been shown that peptide-specific CD8-positive (CD81) or CD41 cytotoxic T cells proliferate as a response to HLA class I or II molecules presenting proteins encoded from e13a2 and e14a2. [7][8][9][10] Bocchia et al 11 assessed the affinity of e13a2 and e14a2 transfusion proteins to HLA class I molecules and found that 4 peptides derived from the e14a2 breakpoint had high or intermediate affinity for HLA A3, A11, and B8 molecules, but this was not true for e13a2, which did not demonstrate any affinity for these HLA class I molecules. The authors suggested that this might play a role in the impaired CD81 cytotoxic T-cell response observed in patients with the e13a2 transcript.…”

Chaperone‐rich cell lysate embedded with BCR‐ABL peptide demonstrates enhanced anti‐tumor activity against a murine BCR‐ABL positive leukemia

“…The BCR/ABL protein is an excellent model to study tumor-specific antigens as it is found in the tumor cells of chronic myelogenous leukemia but not normal tissue. This fusion oncoprotein contains several specific peptides, including the fusion peptide itself, GFKQSSKAL, which has been previously shown to bind to MHC class I and II molecules in mice and humans (44,45,46). It is clearly relevant as a therapeutic target from both chemo-and immunotherapy standpoints (47).…”