Induction of leukemia‐specific antibodies by immunotherapy with leukemia‐cell‐derived heat shock protein 70

Abstract

Cancer immunotherapy using heat shock protein (HSP) derived from autologous tumor requires cluster of differentiation (CD)4+ as well as CD8+ T-cells for the prolongation of patient survival, suggesting that a humoral immune response through CD4 + T-cells is important in addition to cellular immunity. However, the role of humoral responses in HSP-based autologous tumor immunotherapy remains unclear. In the present study, we investigated whether leukemia-specific antibodies and antibodymediated cytotoxicity against autologous leukemia cells have a crucial role in a mouse A20 leukemia model by immunizing A20-derived HSP70. Immunization with A20-derived HSP70 induced the production of anti-A20-antibodies and the antibodies recognized HSP70-binding peptides derived from A20. One of those was a major histocompatibility complex ( (1) HSP70 is one of the HSP localized in the cytoplasm and carries peptides to the endoplasmic reticulum, in which glycoprotein (gp)96, another class of HSP, transports the peptides onto the major histocompatibility complex (MHC) class-I molecules.(2-4) In addition, it is known that HSPpeptide complexes are taken up by the antigen-presenting cells (APC) though the cluster of differentiation (CD)91 receptors expressed on APC, and the peptides bound to these HSP are then presented on the MHC class-I or II molecules.(5,6) Because the tumor-derived HSP bind the tumor-specific antigenic peptides, (5)(6)(7) tumor-derived HSP-antigenic peptide complexes are used for vaccination against cancer. As individual HSP are homogeneous, HSP-based cancer vaccine has the advantage of inducing specific immunity against tumor cells of each different haplotype without the need to identify any tumor-specific antigenic peptides. (5,8) In recent years, clinical efficacies of HSP derived from autologous tumor cells have been reported in several cancer patients, including patients suffering renal cell carcinoma, melanoma or chronic myelogenous leukemia, especially in subgroups of patients with relatively few tumors. (9)(10)(11)(12) Although chemotherapies and autologous stem cell transplantations (SCT) have been performed on many patients with leukemia or lymphoma, clinical results have not been satisfactory because of a relapse owing to the presence of minimal residual disease (MRD) and the lack of a graft-versus-leukemia (GVL) effect, both of which can be overcome by allogeneic transplantation. (13)(14)(15) We have established a mouse model with a minimum amount of leukemia cells after syngeneic bone marrow transplantation, and have reported that the immunization of mice with leukemia-cell-derived HSP70 or gp96 induces leukemia-specific immunities by CD8 positive (+) cytotoxic T-cells (CTL) and prolongs the survival of the mice. (16,17) These findings showed the possibility of a clinical application of HSP-based immunotherapy for patients with leukemia, especially for those with minimal residual leukemia cells after SCT.In HSP-based immunotherapy for cancer, cell-mediated immune response by tumor-specific CD8+ CTL is...

Targeting Hsp70: A possible therapy for cancer

“…Hsp70 derived from A-20 leukemic cells acts as an antigen and induces the production of an A-20-specific antibody, resulting in complement-dependent cytotoxicity against these cells [197]. Further, dendritic cells pulsed with Hsp70 induce immunity against B-16 melanoma, which increases the therapeutic value of a Cox-2 inhibitor [198].…”

Disease‐stabilizing treatment with all‐trans retinoic acid and valproic acid in acute myeloid leukemia: Serum hsp70 and hsp90 levels and serum cytokine profiles are determined by the disease, patient age, and anti‐leukemic treatment

“…The 22 patients included in the second protocol received valproic acid alone for the first 7 days, this drug was thereafter combined with ATRA for days 8-22 and low-dose cytarabine for days [15][16][17][18][19][20][21][22][23][24][25]. Finally, valproic acid was continued as the only drug from day 26.…”

“…HSP70 and HSP90 seem to be the HSPs most commonly expressed at high levels by primary human AML cells [7,11,19]. Previous studies suggest that serum HSP levels may have a prognostic impact in younger AML patients receiving intensive chemotherapy [9,12]; a possible explanation for this could be modulation of anti-leukemic T cell reactivity [20][21][22]. However, one would expect this effect of AML-cell derived HSPs to be further modulated by the cytokine network.…”

“…HSP90 serum levels in patients treated with valproic acid, ATRA, and low dose cytarabine. HSP90 serum levels (ng/ml) were determined for 22 patients before and after treatment with valproic acid (from day 1), oral ATRA (21.5 mg/m 2 twice daily, days[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22], and low-dose subcutaneous cytarabine (corresponding to a total dose 100 mg/m 2 for a 10-day period, days 15-24). The figure presents the serum HSP90 levels before treatment (day 1, 22 samples), treatment with valproic acid plus ATRA (day 15, 15 samples) and after treatment with the triple combination of valproic acid, ATRA, and low-dose cytarabine (day 27, 19 samples).…”

Heat shock protein vaccination and directed IL-2 therapy amplify tumor immunity rapidly following bone marrow transplantation in mice

“…[73][74][75] In contrast to the present studies, 2 to 4 times the amount of gp96 was required, and the first vaccination was administered 2 weeks after HSCT, with subsequent vaccinations after the emergence of thymic-derived T cells. Notably, in our immediate vaccination strategy, although recipient APCs initially contributed to eliciting tumor-reactive CD8 1 T cells (Figure 2A), the response rapidly became singularly dependent on donor B7-expressing APCs ( Figure 2B), which included a critical CD11c 1 CD8a 1 cross-presenting DC population ( Figure 2C) and required perforin-1 ( Figure 2D).…”