SummaryImmunotherapy is an attractive therapeutic option for patients with haematological malignancies. Until recently, the progress in the development of tumour vaccines for haematological malignancies had been slow due to the lack of suitable targets. Cancer-testis (CT) antigens are potentially suitable molecules for tumour vaccines of haematological malignancies because of their high immunogenicity in vivo and their relatively restricted normal tissue distribution. This review evaluates the properties and potential functions of CT antigens. We discuss the expression of CT antigens in patient with haematological malignancies and provide evidence in support of their immunogenicity in vivo in these patients. We also address the role of 'epigenetic' regulation of CT antigens in haematological malignancies and how hypomethylating agents could induce the expression of some of these antigens in tumour cells to overcome the problem of heterogeneity of expression of the antigen within individual tumour specimens. Data implicating the interaction of the promoter genes of some of these CT antigens with the MeCP2 protein also suggest the potential role of the histone deacetylase inhibitors in inducing antigen expression in tumour cells. Finally, we discuss the direction of future research in advancing the development of tumour vaccines for haematological malignancies.
Since most intracellular proteins are expressed with their ligands, ligands of cancer-testis (CT) antigens may also be CT in their distribution. Applying Sperm protein 17 (Sp17) as the bait in a yeast 2-hybrid system of a testicular cDNA library, 17 interacting clones were isolated and all encoded Ropporin, a spermatogenic cell-specific protein that serves as an anchoring protein for the A-kinase anchoring protein, AKAP110. Ropporin showed a very restricted normal tissue gene expression, detected only in testis and fetal liver. Ropporin mRNA could also be detected in tumor cells from patients with multiple myeloma, chronic lymphocytic leukemia and acute myeloid leukemia. Interestingly, expression of Sp17 did not necessarily predict for the expression of Ropporin suggesting that their coexpression in these tumor cells was random rather than coordinated. Ropporin gene expression in tumor cells is associated with the presence of high titer IgG antibodies against Ropporin, suggesting the in vivo translation of the mRNA into protein and the immunogenicity of the protein to the autologous hosts. Using a CT antigen as the bait in a yeast 2-hybrid system may, therefore, identify novel tumor antigen. Our results also suggest that Ropporin is a novel CT antigen in hematologic malignancies. ' 2007 Wiley-Liss, Inc.Key words: yeast two-hybrid; Sp17; ropporin 1; CT antigen Although tumor vaccine is an attractive therapeutic option for patients with hematologic malignancies, clinical progresses have not matched laboratory successes. One reason for the lack of successes in clinical tumor immunotherapy is the heterogeneity of tumor antigen expression within individual tumor specimens. Therefore, successful targeting of one specific tumor antigen may be followed by the emergence of antigen-negative variant tumor cells. Furthermore, clinical successes may also be hampered by the relatively high tumor burden, when compared to the antigen-specific effector cells generated by the tumor vaccine in vivo. Identification of tumor antigens that are coexpressed within a tumor specimen may overcome these problems. These antigens could be used in polyvalent vaccines to produce high effector:target ratios of multiple specificity in vivo and reduce the chance for tumor escape by the emergence of variant tumor cells that do not express one particular antigen.Cancer-testis (CT) antigens are a group of normal testicular proteins aberrantly expressed in cancer cells. 1 Although initially thought to be testicular-specific, further sensitive studies involving real-time PCR have found ''leaky'' expression of many of these antigens in some normal tissues, albeit at a much lower level when compared to that in normal testis and in tumor cells. 2,3 Because of their wide distribution in a number of tumors, including hematologic malignancies, and their primary expression in normal testis, CT antigens represent excellent targets for immunotherapy. The testis is an immune privileged site for two reasons: the apparent lack of HLA class I expression on the su...
Summary Early chronic lymphocytic leukaemia (CLL) is an ideal disease for immunotherapy. We previously showed that SEMG 1 is a cancer‐testis (CT) antigen in CLL. In this study, SEMG 1 was applied as the bait in a yeast two‐hybrid system of a testicular cDNA library. Seven clones were isolated and Protamine (Prm) 1 was identified as a novel CT antigen in early CLL. PRM1 transcripts were detected in 11/41 (26·8%) patients. Prm 1 protein was also expressed but heterogeneously within individual patients. Of the 11 patients expressing Prm 1, four expressed Zap 70 protein and seven did not. These results, therefore, indicate that Prm 1 could potentially be a suitable target for the design of tumour vaccine for patients with early CLL, including for those with poor risk CLL. High titres of Prm 1 IgG antibodies could be detected in 20 of these 41 CLL patients but not in any of the 20 healthy donors (P = 0·0001), suggesting the presence of Prm 1‐reactive immune responses within the immune repertoire of patients with early CLL. Further work is warranted, especially in approaches to upregulate Prm 1 expression, and to determine the role of Prm 1 as an immunotherapeutic target for early CLL.
Most intracellular proteins are expressed with their interacting ligands. If a protein shows restricted normal tissue expression, its interacting ligand will likely also follow a restricted normal tissue expression pattern. We hypothesized that protein molecules interacting with CT antigens may also be testicular restricted and potential CT antigens. Identification of these proteins provides the opportunity for their application in polyvalent tumor vaccines to overcome the problems associated with antigen heterogeneity within a tumor specimen. We have applied two known CT antigens, Sperm protein 17 (Sp17) and SEMG1, as baits in yeast two-hybrid systems of a testicular cDNA library to identify the protein interacting with these two antigens and determine whether the interacting protein are also CT antigens. To do so, we first isolated and amplified cDNA encoding Sp17 and SEMG1. Following successful amplification and sequence confirmation, the cDNAs were sub-cloned into pGBKT7 and transformed into yeast strain AH109 and selected on SD/-Trp plates. Mating was performed between AH109-pGBKT7-Sp17 or pGBKT7-SEMG 1 and pre-transformed human testis cDNA library in yeast strain Y187. Following mating, the culture was first selected on SD/-His/-Leu/-Trp plates and then on SD/-Ade/-His/-Leu/-Trp/X-a -Gal plates. A total of 17 positive clones were isolated using Sp17 and 24 positive clones using SEMG 1 as the bait. Following confirmation of interaction, the colonies were expanded and the the plasmids subjected to sequence identification by nucleotide analysis. All 17 clones isolated using Sp17 encoded Ropporin 1 and all 24 clones isolated using SEMG 1 encoded Protamine 1. Using RT-PCR on total RNA derived from a panel of normal tissues, we demonstrated the very restriction normal tissue expression of Protamine 1 and Ropporin 1, being present only in normal testis, indicating that they are also testicular-specific genes. Analysis of a panel of fresh tumor cells, we showed the aberrant expression of both Protamine 1 and Ropporin 1 in a proportion of hematologic malignancies, including acute myeloid leukemia, multiple myeloma and chronic lymphocytic leukemia, supporting the notion that Ropporin 1 and Protamine 1 are both novel CT antigens in hematologic malignancies. Furthermore, these antigens were also able to elicit high titer B-cell responses in vivo in these patients, suggesting their immunogenicity in the autologous host, even in cancer-bearing patients. Interestingly, the expression of one partner CT antigen within an individual tumor specimen does not necessary predict for the co-expression of the interacting CT antigen. In conclusion, we have described a novel approach to the identification of CT antigens that could be used for immune targeting. This approach could be applied using other known CT antigens to identify other tumor antigens. The lack of a good correlation between the expressions of the partner protein with the interacting protein suggests two important points. First, the aberrant expression of these interacting pair of molecules is not a result of coordinated intracellular regulatory mechanisms but likely due to random processes. Second, if the function of one protein is dependent on the presence of its ligand, then these individual molecules expressed within the tumor cells are unlikely to be of any functional significance in the tumor cells from most patients.
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