The forkhead box M1 transcription factor as a candidate of target for anti‐cancer immunotherapy

Abstract

The present study attempted to identify a target antigen for immunotherapy for cholangiocarcinoma. Forkhead box M1 (FOXM1) was selected as a candidate antigen based on the data of previous cDNA microarray analysis of clinical samples of cholangiocarcinoma. The level of FOXM1 mRNA was more than 4 times higher in cancer cells in comparison to adjacent normal epithelial cells, in all of 24 samples of cholangiocarcinoma tissues. An immunohistochemical analysis also detected FOXM1 protein in the cancer cells but not in the normal cells. Twenty-three human FOXM1-derived peptides predicted to bind to HLA-A2 were analyzed to determine their ability to induce HLA-A2-restricted T cells in HLA-A2 transgenic mice. FOXM1 362-370 (YLVPIQFPV), FOXM1 373-382 (SLVLQPSVKV), and FOXM1 640-649 (GLMDLSTTPL) peptides primed HLA-A2-restricted cytotoxic T lymphocytes (CTLs) in the HLA-A2 transgenic mice. Human CTL lines reactive to these 3 peptides could also be established from HLA-A2-positive healthy donors and cancer patients. Natural processing of the 3 epitopes from FOXM1 protein was confirmed by specific killing of HLA-A2-positive FOXM1-transfectants by peptide-induced CTLs. FOXM1 is expressed in various types of cancers and it is also functionally involved in oncogenic transformation and the survival of cancer cells. Therefore, FOXM1 may be a suitable target for immunotherapy against various cancers including cholangiocarcinoma.Cholangiocarcinoma is a devastating malignancy, which is difficult to diagnose and treat. Unfortunately, only a few patients are considered suitable for surgery, and chemotherapy and radiotherapy have not yielded substantial improvements in the survival rate. The overall survival rate is poor, with less than 5% of patients surviving upto 5 years. There has been no significant change in this rate over the past 30 years. 1 Recent studies have identified some therapeutic molecular targets in cholangiocarcinoma in preclinical studies, thus supporting the therapeutic potential of selected targeting strategies against cholangiocarcinoma. 2 The results were encouraging, although they were obtained from in vitro studies and tumor cell xenograft models. Therefore, novel therapeutic strategies for cholangiocarcinoma are urgently needed.In cancer immunotherapy, effective induction of cytotoxic T lymphocytes (CTLs) by tumor-associated antigen (TAA) has shown promising results. 3 The utilization of CTLs elicited by TAA is an ideal therapeutic approach, if they specifically attack tumor cells expressing the antigen and reveal little or no adverse effects on normal cells. The development of cDNA microarray technologies, coupled with genome information, has provided comprehensive profiles of the gene expression of malignant cells, which have been compared to those of normal cells. 4,5 TAAs should be expressed excessively and preferentially by the tumor cells but not by the

Overexpression of FoxM1 offers a promising therapeutic target in diffuse large B-cell lymphoma

“…These data agree with another report that showed absence or minimal expression of FoxM1 in normal tissue from various organ sites as compared to their cancer counterparts. 42 Our data also showed that proliferative marker Ki67 was strongly associated with FoxM1 overexpression suggesting that FoxM1 deregulation may be driving the survival and proliferation of DLBCL cells.…”

Immunotherapy based on dendritic cells pulsed with CTPFoxM1 fusion protein protects against the development of hepatocellular carcinoma

“…Fourthly, clinicopathologic studies suggest that FoxM1 expression correlated with poorly-differentiated HCC tumors with intrahepatic metastasis, which is a leading cause of post-surgical recurrence and low survival rate [20, 29]. Finally, silencing of FoxM1 expression could inhibit human hepatocellular carcinoma growth [30], and FoxM1 has been reported an underlying therapeutic target because it can be presented to cell surface by tumor cells [31]. Therefore, FoxM1 is considered as a novel therapeutic target for HCC drug therapy.…”

Identification of Promiscuous KIF20A Long Peptides Bearing Both CD4+ and CD8+ T-cell Epitopes: KIF20A-Specific CD4+ T-cell Immunity in Patients with Malignant Tumor

“…In brief, the frequency of peptide-specific CD4 þ T cells producing [24][25][26]. All mAbs were used at a final concentration of 5 mg/mL.…”