Targeting Positive Regulatory Domain I-Binding Factor 1 and X Box-Binding Protein 1 Transcription Factors by Multiple Myeloma-Reactive CTL

Abstract

Growing evidence indicates that multiple myeloma (MM) and other malignancies are susceptible to CTL-based immune interventions. We studied whether transcription factors inherently involved in the terminal differentiation of mature B lymphocytes into malignant and nonmalignant plasma cells provide MM-associated CTL epitopes. HLA-A*0201 (A2.1) transgenic mice were used to identify A2.1-presented peptide Ag derived from the plasma cell-associated transcriptional regulators, positive regulatory domain I-binding factor 1 (PRDI-BF1) and X box-binding protein 1 (XBP-1). A2.1-restricted CTL specific for PRDI-BF1 and XBP-1 epitopes efficiently killed a variety of MM targets. PRDI-BF1- and XBP-1-reactive CTL were able to recognize primary MM cells from A2.1+ patients. Consistent with the expression pattern of both transcription factors beyond malignant and nonmalignant plasma cells, PRDI-BF1- and XBP-1-specific CTL activity was not entirely limited to MM targets, but was also associated with lysis of certain other malignancies and, in defined instances, with low-to-intermediate level recognition of a few types of normal cells. Our results also indicate that the A2.1-restricted, PRDI-BF1- and XBP-1-specific human CD8+ T cell repertoire is affected by partial self tolerance and may thus require the transfer of high-affinity TCR to break tolerance. We conclude that transcription factors governing terminal cellular differentiation may provide MM- and tumor-associated CTL epitopes.

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

“…Lotz et al 39 suggested that the HLA-A2-restricted XBP1-specific human T cell repertoire is affected by partial self-tolerance. We examined whether the heteroclitic XBP1 peptides are able to break T-cell tolerance to this plasma cell-specific self-antigen.…”

PU.1 Regulates Positive Regulatory Domain I-Binding Factor 1/Blimp-1 Transcription in Lymphoma Cells

“…This provides support that therapeutic approaches to trigger endogenous PRDM1 expression are feasible and could be a viable approach to induce apoptosis in lymphoma cells. Furthermore, PRDI-BF1 has been shown to be an important target in immunotherapy of myeloma by induction of PRDI-BF1-specific cytotoxic T cells, an approach which could also be exploited to kill lymphomas after PRDI-BF1 induction (41). …”

Immunoglobulin light chain, Blimp‐1 and cytochrome P4501B1 peptides as potential vaccines for AL amyloidosis

“…Blimp‐1 was chosen as a third target (and second self‐antigen) in our attempt to triangulate CTL responses against plasma cells primarily because of its upregulation in that lymphocyte subset and its critical role in plasma cell development and thereby in AL amyloidosis pathogenesis. The prediction that CTL generated with Blimp‐1‐derived peptide(s) would be clinically effective is supported by the ability of CTL generated in mice with HLA‐A2‐binding human Blimp‐1‐derived peptides, including one peptide that shares the T‐cell‐binding domain with our murine Blimp‐1 470−478 (FPRL), to lyse HLA‐A2 + human myeloma cell lines and primary plasma cells 54 . Although the human Blimp‐1 peptides in Lotz et al 54 were not self‐antigens in the HLA‐transgenic mice, these results demonstrate that Blimp‐1 peptides are processed and presented by malignant human plasma cells such that they can be recognized by peptide‐induced CTL.…”

“…The prediction that CTL generated with Blimp‐1‐derived peptide(s) would be clinically effective is supported by the ability of CTL generated in mice with HLA‐A2‐binding human Blimp‐1‐derived peptides, including one peptide that shares the T‐cell‐binding domain with our murine Blimp‐1 470−478 (FPRL), to lyse HLA‐A2 + human myeloma cell lines and primary plasma cells 54 . Although the human Blimp‐1 peptides in Lotz et al 54 were not self‐antigens in the HLA‐transgenic mice, these results demonstrate that Blimp‐1 peptides are processed and presented by malignant human plasma cells such that they can be recognized by peptide‐induced CTL. Importantly, this conclusion is supported by our studies in which modest but statistically significant decreases in plasma cell percentages were observed in the spleens, lymph nodes and bone marrow of mBlimp‐1 470−478 ‐immunized mice and a significant decrease in absolute number of splenic plasma cells was documented (Figure 6).…”