Immunotherapy is theoretically an attractive therapeutic option for patients with hematological malignancies. Various laboratory studies suggested the importance of the choice of tumor antigen for successful immunotherapy. Cancer-testis antigens (CTAs) are potentially suitable molecules for tumor vaccines of hematological malignancies because of their high immunogenicity in vivo, even in cancer-bearing patients, and their relatively restricted normal tissue distribution. Tumor cell kill using a CTA-based immunotherapy will, therefore, be more specific and associated with less toxicities when compared to chemotherapy. Many CTAs have been identified in various hematologic malignancies. In this review, we will take the readers through the journey of hopes and the disappointments arisen from the discovery of CTAs. We will describe the features of CTAs and their expression in hematologic malignancies. We will also discuss the mechanisms regulating the expression of these CTAs, from a primary regulatory mechanism involving DNA methylation to secondary controls by cytokines. Finally, we will address the potential obstacles that will prevent the successful use of CTAs as targets for tumor immunotherapy.

Semenogelin (SEMG) I is a Cancer-Testis antigen expressed in myeloma cells. SEMG I expression is upregulated by IL-4, IL-6 and 5-azacytidine. In this study, we set out to define the core promoter sequence needed for the expression of SEMG I in myeloma cells. We found that nucleotide sequences spanning the two putative GATA-1 binding domains are vital for the primary regulation of SEMG I promoter function while the other parts of the promoter sequence are responsible for the fine adjustment of the core promoter function. The core promoter sequence is responsive to the enhancing effect of IL-4 and IL-6.

Semenogelin (SEMG) I is a Cancer-Testis (CT) antigen that we have found to be expressed in myeloma cells. In this study, we set out to determine whether the expression of SEMG I could be upregulated pharmacologically. We found that SEMG I expression in myeloma cells can be upregulated by 5-azacytidine, IL-4 and IL-6. The mechanisms of SEMG I gene upregulation by 5-azacytidine is unclear since there was no correlation between the methylation of the single CpG dinucleotide at position -11 and SEMG I expression. Both IL-4 and IL-6 appeared to enhance SEMG I expression through increasing its promoter function.

Summary

Early chronic lymphocytic leukemia (CLL) is an ideal disease for immunotherapy. We previously showed that SEMG 1 is a Cancer-Testis (CT) antigen in CLL. In this study, we applied SEMG 1 as the bait in a yeast two-hybrid system of a testicular cDNA library. We isolated seven clones and identified Protamine (Prm) 1 as a novel CT antigen in early CLL. Prm 1 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 tumor vaccine for patients with early CLL, including for those with poor risk CLL. High titers 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 immune repertoire of patients with early CLL. Further work is warranted, especially in approaches to upregulate Prm 1 expression, to determine the role of Prm 1 as an immunotherapeutic target for early CLL.