Identification of HLA-A*0201-Presented T Cell Epitopes Derived from the Oncofetal Antigen-Immature Laminin Receptor Protein in Patients with Hematological Malignancies

Abstract

The oncofetal Ag immature laminin receptor (OFA-iLR) is a potential target molecule for immunotherapeutic studies in several tumor entities, including hematological malignancies. In the present study, we characterize two HLA-A*0201-presented epitopes eliciting strong OFA-iLR peptide-specific human cytotoxic T cell (CTLs) responses in vitro. Both allogeneic HLA-A*0201-matched and autologous CTLs recognized and killed endogenously OFA-iLR-expressing tumor cell lines and primary malignant cells from patients with hemopoietic malignancies in an MHC-restricted fashion but spared nonmalignant hemopoietic cells. Spontaneous OFA-iLR peptide-specific T cell reactivity was detectable in a significant proportion of leukemia patients. Interestingly, in patients with chronic lymphocytic leukemia and multiple myeloma but not in those with acute myeloid leukemia, significant frequencies of OFA peptide-specific CTLs could be detected in an early stage of disease but disappeared in patients with progressive disease. The identification of OFA-iLR-derived peptide epitopes provides a basis for tumor immunological studies and therapeutic vaccination strategies in patients with OFA-iLR-expressing malignancies.

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

“…25 CD8 þ T cells specific for G250/CAIX [24][25][26][27][28][29][30][31][32] , G250/CAIX 254-262 and RHAMM [165][166][167][168][169][170][171][172][173] are also regularly detected in the peripheral blood of AML patients, with frequencies of 60%, 13% and 47%, respectively. 25 In a series of 15 AML patients, Siegel et al 22 observed spontaneous T-cell immune responses to different HLA-A*0201-restricted T-cell epitopes derived from OFA-iLRP, including iLR1 [59][60][61][62][63][64][65][66][67][68] (6/15) …”

“…Their expression is repressed in normal adult tissues, making it unlikely that oncofetal antigen-targeted immunotherapy elicits autoimmunity. 21,22 ETO, also known as MTG8, which is found to be overexpressed in leukemic cells carrying the t(8;21) chromosomal translocation, 23 is another example of a relatively tumor-specific LAA. Physiological expression of MTG8 appears to be predominantly restricted to the human brain and heart.…”

Oncofetal antigen/immature laminin receptor protein in pregnancy and cancer

“…However, immunization with iLRP in a mode that only or at least primarily induces Th1 and cytotoxic CD8 T cells could be used in cancer immunotherapy. One such mode would be by immunizing with autologous dendritic cells pulsed with iLRP or iLRP peptides that induce Th1 and cytotoxic T cells, but not with IL-10-secreting CD8 T cells [47,49]. The in vivo antitumor efficacy of iLRP was also demonstrated by immunization of BALB/c mice with recombinant iLRP entrapped in liposomes and challenge with a tumorigenic dose of murine fibrosarcoma MCA1315 cells [50].…”

“…iLRP is important to the tumor cells for invasion and metastasis [26], and most metastatic human tumors express increased amounts of this protein [43]. While early studies were confined to rodent tumor and pregnancy models, recent work has been focused on human malignancies, such as head and neck cancer [44], breast cancer [31], renal cancer [32,45], hematological malignancies [33,[46][47][48], and several other types of cancer [34].…”

In-vivo detectable antibodies directed against the oncofetal antigen/immature laminin receptor can recognize and control myeloma cells—clinical implications

“…6,7 In contrast, OFA/iLR is re-expressed on a broad range of malignancies including some hematological tumor entities. [8][9][10] By utilizing a mouse anti-OFA/iLR monoclonal antibody (Dr J Coggin, Mobile, Al, USA) we show that OFA/iLR is frequently expressed on the surface of malignant plasma cells of patients with MGUS, MM and plasma cell leukemia (Figures 1a and b). For immunohistochemical staining Letters to the Editor and flow cytometry analysis goat anti-mouse immunoglobulin as a secondary antibody coupled to alkaline phosphatase (panel a) or to FITC (panels b and c) was used.…”