Immediate Early Response Gene X-1, a Stress-Inducible Antiapoptotic Gene, Encodes Cytotoxic T-Lymphocyte (CTL) Epitopes Capable of Inducing Human Leukocyte Antigen-A33-Restricted and Tumor-Reactive CTLs in Gastric Cancer Patients

Abstract

Peptide-based vaccine therapy, which is designed to elicit T-cell immunity against tumors, is an attractive approach for the treatment of cancer patients. To provide a scientific basis for peptide therapy, an increasing number of CTL-directed peptides have been identified, and some of them have been tried as antigen-specific immunotherapy in the past decade. Only a few studies, however, have been performed on such peptides restricted with alleles other than HLA-A2 and -A24. In the present study, we show that immediate early response gene X-1 (IEX-1), a stress-inducible protein associated with the regulation of cell proliferation and apoptosis, produces antigenic epitopes recognized by 850B-CTLs, HLA-A33-restricted CTLs newly established from T cells infiltrating into gastric adenocarcinoma. The IEX-1 gene was highly expressed in most cell lines and tissues from various types of cancer at both the mRNA and protein levels. However, it was not expressed at the protein level in any normal epithelium or connective tissues tested. Three IEX-1-derived peptides at positions 47-56, 61-69, and 65-73, which were recognized by the 850B-CTLs, could induce CD8 ؉ peptide-specific CTL reaction to tumor cells from HLA-A33؉ gastric cancer patients and other epithelial cancer patients, but not from healthy donors, in an HLA class I-restricted manner. Because increased expression of IEX-1 is suggested to be involved in the resistance to apoptosis and in the proliferation of cancer cells, these antigenic peptides could be potent candidates for peptide-based specific immunotherapy against HLA-A33 ؉ gastric cancer and other epithelial cancers.

Ran, a Small GTPase Gene, Encodes Cytotoxic T Lymphocyte (CTL) Epitopes Capable of Inducing HLA-A33–restricted and Tumor-Reactive CTLs in Cancer Patients

“…The parental HLA-A33-restricted and tumor-reactive 850B-CTL line was established from the TILs of patient with scirrhous-type gastric adenocarcinoma (HLA-A*2402/A*3303, B7/B44, and Cw7/ Cw14) by incubating TILs with interleukin 2 alone for Ͼ50 days by methods reported previously (13). Briefly, the patient's TILs were incubated with a culture medium (45% RPMI 1640, 45% AIM-V medium; Invitrogen, San Diego, CA; 10% FCS with 100 units/mL interleukin 2).…”

“…In contrast to the many reports on epitope peptides recognized by HLA-A2 or HLA-A24 CTLs (8 -10), information on the antigens and peptides recognized by HLA-A33-restricted CTL is very limited (11)(12)(13). This lack of information has been hampering the development of peptide-based specific immunotherapy for HLA-A33 ϩ cancer patients, despite the relatively wide expression of the HLA-A33 allele in people of various ethnicities (14% of Asians, 4% of Caucasians, and 16% of blacks; refs.…”

“…14, 15). To identify CTL epitope peptides in HLA-A33 ϩ cancer patients, we established a HLA-A33-restricted CTL line from the tumorinfiltrating lymphocytes (TILs) of a patient with scirrhous-type gastric adenocarcinoma, and identified a gene, Ran (16,17), as a gene that codes for tumor-associated antigen (13). We have demonstrated in this study that the two Ran-derived peptides are capable of inducing HLA-A33-restricted CTL activity reactive to tumor cells in epithelial cancer patients.…”

Ikaros increases normal apoptosis in adult erythroid cells

“…This suggests that they are most likely anti-apoptotic in most hematopoietic cells. Similarly, another gene that is upregulated in Ikaros-null mice, immediate-early protein (IER3, IEX-1), has been associated with both increased and decreased apoptosis in cells in vitro [30][31][32] but has been shown to be associated with decreased T-cell apoptosis and increased incidence of T-cell lymphomas in vivo in transgenic mice overexpressing IER3 [33]. Again this suggests an antiapoptotic role for this protein in hematopoietic cells.…”

IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation

“…However, since IER3 is a multifunctional factor, additional work is required to define whether this protein exerts additional protumoral effects through interference with other signaling pathways, in particular NF-κB (10,48) and PI3K/AKT (17). Similarly, with respect to cellular mechanisms, it is possible that this protein additionally modulates pancreatic carcinogenesis by modifying immunological responses (49,50) and apoptosis (10,11,28,51), which are well-characterized players in the process of pancreatic cell transformation. Thus, our present findings not only extend the existing knowledge in the field, but also generate the rational for additional studies.…”