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Available online atwww.sciencedirect.com

ScienceDirect

j o u r n a l h o m e p a g e :w w w . e l s e v i e r . c o m / l o c a t e / j d s r

Review Article

Cancer/testis antigens: A prospective

reagent as diagnostic and

immunotherapeutic targets for squamous

cell carcinoma of the head and neck

Shohei Domae

a,∗

, Toshiro Ono

b

, Akira Sasaki

a

aDepartment of Maxillofacial Surgery, Okayama University Graduate School of Medicine,

Dentistry and Pharmaceutical Science, 2-5-1 Shikata-cho, Okayama 700-8525, Japan

bDepartment of Radiation Research, Advanced Science Research Center, Okayama University,

2-5-1 Shikata-cho, Okayama 700-8558, Japan

Received 31 January 2014; received in revised form 28 May 2014; accepted 13 June 2014

KEYWORDS Cancer/testis antigen; SEREX; Antibody response; Squamous cell carcinoma of the head and neck

Summary Numerous tumor antigens have so far been identified from various tumors using the serological identification of antigens by recombinant expression cloning (SEREX) method. Among them, cancer/testis (CT) antigens are considered promising target molecules for immunother-apy for patients with various cancers. We performed several SEREX analyses of various cancers to identify CT antigens, including gastric adenocarcinoma, lung adenocarcinoma, and colon cancer, and consequently identified additional CT antigens, such as XAGE-1, CCDC62-2, GKAP1, and TEKT5. However, although SEREX analysis of squamous cell carcinoma of the head and neck (HNSCC) has been performed several times, only a few CT or HNSCC specific antigens have yet been isolated. Compared with other tumors, a small number of studies have been reported on the antigen proteins specific to HNSCC. We here reported the expression of selected CT anti-gens and their immunogenicity in patients with HNSCC. The results obtained suggested that CCDC62-2, GKAP1, and TEKT5 are immunogenic in HNSCC and also demonstrated their poten-cies as diagnostic markers for patients with HNSCC in combination with other CT antigens such as NY-ESO-1, MAGE-A3, and MAGE-A4.

© 2014 Japanese Association for Dental Science. Published by Elsevier Ltd.

Corresponding author. Tel.: +81 86 235 6702; fax: +81 86 235 6704.

E-mail address:sdomae@md.okayama-u.ac.jp(S. Domae).

http://dx.doi.org/10.1016/j.jdsr.2014.06.001

1882-7616 © 2014 Japanese Association for Dental Science. Published by Elsevier Ltd.

Open access under CC BY-NC-ND license.

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1. Introduction... 92

2. CT antigens ... 92

3. SEREX ... 93

4. CT genes and families ... 94

4.1. MAGE... 94 4.2. NY-ESO-1 ... 94 4.3. SSX ... 94 4.4. OY-TES-1 ... 95 4.5. AKAP3 ... 95 4.6. XAGE-1 ... 95 4.7. CCDC62-2... 95 4.8. GKAP1 ... 95 4.9. TEKT5 ... 95

5. Expression and humoral response of CT antigens to HNSCC ... 96

6. Conclusion ... 97

Conflict or interest ... 97

Acknowledgements ... 97

References ... 98

1. Introduction

The incidence of squamous cell carcinoma of the head and neck (HNSCC) is more than 20,000 new cases per year in Japan and ∼500,000 cases annually worldwide. Surgi-cal resection is commonly performed followed by combined chemotherapy or radiotherapy. However, the 5-year sur-vival rates of patients with this cancer have remained at approximately 50% for the past 2 decades, in spite of advances in surgical procedures as well as various combi-nations of chemotherapeutic agents[1,2]. Therefore, the development of new therapeutics and their integration into current forms of therapy remain a major goal for the future. Recent progresses in tumor immunology based on the molecular identification of tumor antigens may allow immunotherapy to become another promising treatment to improve the outcomes of patients with HNSCC. Following the introduction of the T cell epitope cloning technique by Boon et al.[3], numerous antigens coding for immunogenic sequences have been identified in different tumor types, including MAGE families in malignant melanoma[4]and NY-ESO-1 in esophageal cancer[5]. Cancer/testis (CT) antigens have become promising targets for the diagnosis of and immunotherapy for patients with various tumors because of their unique expression patterns[6]. Compared with other tumors, a small number of studies have been reported on the antigen proteins specific to HNSCC[7,8]. We here reported the expression of selected CT antigens and their immuno-genicity in patients with HNSCC.

2. CT antigens

The defining characteristics of CT antigens are high levels of expression in male germ cells such as spermatogonial stem cells, spermatogonia, spermatocytes, spermatids, and spermatozoa during spermatogenesis in the testis, and lack of expression in normal tissues[9]. The expression of CT antigens has also been reported in the ovary and pla-centa[10,11]. The genes of CT antigens are activated and

Table 1 List of known CT antigens and CT antigen families.

CT antigen No. of genes Chromosome

MAGE-A 11 Xq28 BAGE 5 13 GAGE 8 Xp11.4-11.2 SSX 9 Xp11.2 NY-ESO-1/LAGE-1 2 Xq28 SCP1 1 1p13 CT7/MAGE-C1 1 Xq26-27 CT8/HOM-TES-85 1 Xq24 CT10 1 Xq27 cTAGE 5 18p11 XAGE-1 5 Xp11.21-22 OY-TES-1 1 12p13.31 AKAP3 1 12p13.3 CCDC62-2 1 12q24.31 GKAP1 1 9q21.32 TEKT5 1 16p13.13

aberrantly expressed in a wide range of different tumor types and have been shown to be antigenic in tumor-bearing patients [12]. CT antigens are now classified as X-CT and non-X-CT based on whether the gene is located on the X chromosome (Table 1). X-CT antigens are often organized in well-defined clusters to constitute multigene families [13,14]. However, genes encoding non-X-CT antigens are dis-tributed throughout the genome and are mostly single-copy genes. Since different CT antigens are expressed during dif-ferent stages of spermatogenesis (Fig. 1), their function may be versatile, e.g. the regulation of mitotic cycling in sper-matogonia, an association with the meiotic cycle in sperma-tocytes, and finalizing acrosome maturation in sperm.

More than 110 genes or gene families coding for CT antigens have been identified to date by several method-ologies [15], such as T-cell epitope cloning, serological identification of antigens by recombinant expression cloning (SEREX), representational difference analysis (RDA), DNA

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Figure 1 Expression of CT antigens in germ cells during spermatogenesis. The unique expression patterns of MAGE-A, NY-ESO-1, CCDC62-2, and OY-TES-1 are shown. MAGE-A and CCDC62-2 protein expression is also shown in human adult testis tissues.

microarray analysis, and bioinformatics. The T-cell epitope cloning method developed by Boon et al. in 1991 resulted in the discovery of MAGE-A1, BAGE, and GAGE1[3,16,17], and RDA led to the cloning of LAGE-1, MAGE-E1, and SAGE [18—20]. MAA-1A was identified using DNA microarray analysis[21]. More recently, bioinformatics-based analysis resulted in the cloning of BRDT, OY-TES-1, PAGE5, LDHC, and TPTE [22—25]. Of these methods, SEREX appears to be effective for the identification of CT antigens. SSX2, SYCP-1, and NY-ESO-1 were isolated using cDNA libraries from cancer or normal testis tissues[26—28]. Additional CT antigens, such as XAGE-1, CCDC62-2, GKAP1, and TEKT5, were identified in our SEREX analysis[29—32].

3. SEREX

SEREX was developed in 1995 by Pfroundschuh et al. to combine serological analysis with antigen cloning tech-niques in order to identify human tumor antigens eliciting high-titer immunoglobulin G (IgG) antibodies [33]. The SEREX technique is shown schematically in Fig. 2. In brief, serum samples, which had been diluted 1:10, were preabsorbed with lysate from Escherichia coli and

bacteriophage-infected E. coli coupled to sepharose 4B. Nitrocellulose membranes containing the phage plaques at a density of approximately 4000 pfu/140 mm plate were incu-bated overnight at room temperature with the preabsorbed autologous serum, which had been diluted 1:200. Reacted clones were detected using peroxidase-conjugated goat anti-human IgG and visualized with 3-3-diaminobenzidine. Positively-reacted clones were subcloned to monoclonality, purified, and excised in vivo to pBK-CMV plasmid forms. Plas-mid DNA was prepared and the nucleotide sequence of cDNA inserts was determined by a DNA sequencer.

SEREX utilizes the sera of cancer patients, which con-tain antibodies against a various tumor antigens, to screen for tumor antigens in cDNA expression libraries constructed from tumor tissues or cell lines. In the initial set of experiments, Sahin et al. analyzed melanoma, renal cell carcinoma, astrocytoma and Hodgkin lymphoma, which resulted in the isolation of a large number of genes[34]. These included MAGE-A1 and tyrosinase, two antigens pre-viously shown to be targets for cytotoxic T lymphocytes, which indicated that protein antigens that elicit antibody responses in cancer patients are likely to have elicited simul-taneous T cell responses [33]. This finding prompted the large scale SEREX screening of various tumor types, and led

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Figure 2 Schematic representation of the SEREX method.

to the identification of more than 1000 SEREX-defined anti-gens. It included several CT antigens such as MAGE-A, SSX, NY-ESO-1, SCP1, and CAGE-1. We more recently identified additional CT antigens, such as XAGE-1, CCDC62-2, GKAP1, and TEKT5 using this method. SEREX has been performed to screen HNSCC, and several HNSCC-specific antigens have been isolated [35,36]. A screening of a testicular cDNA expression library with HNSCC patient sera has led to the identification of a CT antigen, KM-HN-1[37].

4. CT genes and families

4.1. MAGE

Boon and colleagues reported the first successful cloning of a human tumor antigen in 1991 using the melanoma cell line MZ2-MEL and autologous CTL clones, termed MAGE-1 (subsequently re-named as MAGE-A1). It elicited a spon-taneous CTL response in an autologous melanoma patient [3]. Boon et al. identified MAGE-A3, another member of the MAGE-A family, using the same strategy. Since then, the MAGE family has expanded to include over 60 genes[38]. An mRNA expression analysis revealed that MAGE-A genes were expressed in the testis, but not in other normal adult tissues. These genes have also been shown to be expressed in various cancers, including HNSCC. MAGE-A3 is frequently expressed in melanoma, non-small-cell lung cancer, bladder cancer, and liver cancer[39—41]. Its tumor specificity makes it a potentially safe and valuable target for immunotherapy.

Several clinical trials have tested peptide-based vaccines and recombinant protein vaccines in melanoma patients and lung cancer patients[42—44].

4.2. NY-ESO-1

NY-ESO-1 was originally identified in esophageal cancer by Chen et al., who performed SEREX on autologous patient serum [5]. NY-ESO-1 belongs to a family of at least two genes, NY-ESO-1 and LAGE-1, mapped in tandem on chro-mosome Xq28. NY-ESO-1 has been the focus of increasing attention because of its strong immunogenicity and has emerged as a prototype of CT antigens. A spontaneous NY-ESO-1-specific antibody response has frequently been observed in patients with various types of advanced stage tumors expressing NY-ESO-1[45,46]. Clinical trials using the NY-ESO-1 peptide, protein, and viral constructs as cancer vaccines have successfully reported the efficient induction of antibodies, and CD4 and CD8 T cell responses[47—49].

4.3. SSX

SEREX screening of a testicular cDNA expression library with sera from melanoma patients led to the identifica-tion of HOM-MEL-40[33], a gene identical to the synovial

sarcoma/X breakpoint 2 gene (SSX-2) involved in t (x: 18)

translocation in synovial sarcoma [50]. The SSX family is composed of at least 9 SSX genes, all of which are located on chromosome Xp11.2. SSX2 and 4 genes are frequently

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expressed in tumor tissues. SSX proteins were shown to be localized to the nuclei of spermatogonia and early sperma-tocytes in the human testis. Anti-SSX1, 2, 3, and 4 antibodies have been detected in patients with various types of tumors, including melanoma, colon, breast, and ovarian cancers [51,52]. However, clinical trials using SSX proteins as vac-cines have been unsuccessful.

4.4. OY-TES-1

OY-TES-1 was shown to be a member of CT antigen family by Ono et al. [23]. This gene is located on chromo-some 12p13.31 and encodes the human homologue of the proacrosin binding protein sp32 precursor, which was ini-tially detected in other mammal species, such as the pig and mouse. sp32 is located in the sperm acrosome and appears to function as a binding protein to proacrosin for the packaging and condensation of acrosin zymogen in the acrosomal matrix. OY-TES-1 is known to be expressed in a range of different tumor types, including bladder, breast, lung, liver, colon, prostate, and ovarian cancers. A serological survey of 362 patients with a range of dif-ferent cancers revealed an antibody to OY-TES-1 in 25 patients. The anti-OY-TES-1 antibody was detected in∼10% of ovarian cancer patients whose tumors expressed the antigen. A previous study reported that high expression lev-els of OY-TES-1 in ovarian cancers correlated with survival times and faster relapses among ovarian cancer patients [53]. These findings indicated that OY-TES-1 could be a target for immunotherapy [54]. The down-regulation of

OY-TES-1 expression in mesenchymal stem cells was more

recently shown to cause cell cycle arrest and a decrease in migration, which indicated that OY-TES-1 may influ-ence the biological behavior of mesenchymal stem cells [55].

4.5. AKAP3

A-kinase anchoring proteins (AKAPs) are a group of struc-turally diverse proteins that bind to the regulatory subunit of PKA, and are signaling scaffolds that contribute to various aspects of cAMP signaling [56]. AKAP-mediated PKA acti-vation was previously shown to inhibit cell growth in the muscle and T lymphocytes[57,58]. AKAP3 is a testis-specific protein that is exclusively expressed in round spermatids. We previously demonstrated that AKAP3 was a CT antigen, and also that the expression of AKAP3 mRNA was marked in ovarian cancer and correlated with the histological grade and clinical stage of the tumor. We also found that AKAP3 mRNA expression was an independent and favorable pro-gnostic factor in patients with poorly differentiated ovarian cancer[59].

4.6. XAGE-1

XAGE-1 was originally identified by EST database mining and found to be highly expressed in normal testis and Ewing’s sarcoma[60]. The XAGE-1 gene is located on chromosome Xp11.21-22, consists of 4 exons, and shows homology to

GAGE/PAGE genes. Four transcript variants, XAGE-1a, b, c

and d, have been identified to date. Of these, XAGE-1b was shown to be the major transcript[61]. Using SEREX anal-ysis, Ali Eldib et al. identified XAGE-1b as the dominant antigen recognized by serum from a lung adenocarcinoma patient from an autologous tumor cell line established from malignant pleural effusion as a cDNA library source[29]. Approximately 10% of lung adenocarcinoma patients showed antibody responses. CD4 and CD8 T cell responses against XAGE-1b were also elicited in antibody-positive lung adeno-carcinoma patients, which demonstrated that XAGE-1b is a promising antigen for immunotherapy against lung adeno-carcinoma[62].

4.7. CCDC62-2

SEREX analysis identified coiled-coil domain containing 62 (CCDC62) in a testicular cDNA library and serum obtained from a gastric adenocarcinoma patient in whom primary cancer had regressed once and most liver metastases had transiently disappeared. The CCDC62 gene consists of 13 exons and is located on chromosome 12q24.31. It has 2 splice variants of 2481 bp (CCDC62-1, NM 032573) and 3044 bp (CCDC62-2, NM 201435), which encode proteins of 682 amino acids and 684 amino acids, respectively. RT-PCR analysis revealed that the expression of both vari-ants was restricted to the testis in normal adult tissues. The expression of CCDC62-1 mRNA was absent, whereas that of CCDC62-2 mRNA was observed in several types of tumors. In a large scale ELISA survey of 191 serum sam-ples collected from patients with several types of cancer, 13 patients were found to have produced an antibody to the CCDC62-2 protein, including stomach cancer. Western Blot analysis revealed reactions against recombinant CCDC62-2 molecules. CCDC62-2 was identified as a novel CT antigen that is immunogenic in cancer patients[30].

4.8. GKAP1

G-kinase anchoring protein 1 (GKAP1) was also identified by SEREX analysis using a testicular cDNA library and serum obtained from a gastric adenocarcinoma patient. It was iso-lated by a yeast two-hybrid system using a mouse embryo library and reported as the male germ cell-specific 42-kDa protein, GKAP42[63]. We successfully cloned human GKAP1 cDNA and demonstrated that the expression of GKAP1 mRNA was the highest in the testis of normal adult tissues and in various cancers[30,31]. GKAP1 functions as an anchor-ing protein for cGK-I␣ and appears to be similar to AKAP (A kinase anchoring protein), which binds to cAK via its regu-latory subunits.

4.9. TEKT5

Hanafusa et al. performed SEREX analysis on colon cancer, and identified the novel CT antigen, Tektin 5 (TEKT5)[32]. TETKs are composed of a family of filament-forming pro-teins in the male germ cell-lineage in centrioles and basal bodies and within ciliary and flagellar doublet microtubules [64]. They were originally isolated from sea urchin sperm. Five types of mammalian Tektins have been identified in

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Figure 3 Protein expression of CT antigens in a HNSCC tissue sample. A HLA class I positive HNSCC specimen was immunohis-tochemically stained with MAGE-A (mAb 6C1), NY-ESO-1 (mAb E978), XAGE-1b (mAb USO 9-13), CCDC62-2 (mAb 6212-1), and CD8 (mAb C8/144b).

various animals, including the mouse, rat, and human[65]. TEKT5 was initially identified in the rat. It is present in sperm flagella, plays an important role in flagella formation dur-ing spermiogenesis, and has also been implicated in sperm motility. The human TEKT5 gene consists of 7 exons and is located on chromosome 16p13.13. The expression of TEKT5 mRNA was restricted to the testis in normal adult tissues. It was detected in several types of cancers, including colon, gastric, liver, lung, and prostate cancers, but not in HNSCC. cDNA microarray analysis revealed that the expression of

TEKT5 was higher in 2 of 3 colon cancer tissues than in

nor-mal tissue. It was also up-regulated by more than 3-fold in 50% of the lung cancer specimens examined. Thus, TEKT5 has a classical future as a CT antigen. In our survey of 101 cancer patients with several types of cancer, 13 patients were found to have produced an antibody to the TEKT5 pro-tein. No reactivity was observed in sera from healthy donors. TETK5 appears to have high immunogenic potential in terms of antibody frequency[32].

5. Expression and humoral response of CT

antigens to HNSCC

We evaluated the patterns and levels of expression of 8 CT genes by RT-PCR from a panel of primary HNSCC. Over 50% of the tumors examined expressed at least 1 CT gene. The coexpression of two or more genes was detected in 23% of HNSCC. The most frequently expressed gene was MAGE-A4 (32%), followed by MAGE-A3 (24%), GKAP1 (18%), MAGE-A1 (13%), CCDC62-2 (12%), SSX-2 (11%), XAGE-1b (7%), and

NY-ESO-1 (3%)[31]. Using monoclonal antibodies, the expression of CT antigen proteins in multigene-expressed HNSCC tissue was analyzed using an immunohistochemical technique. The heterogeneous expression of CCDC62-2 and MAGE-A proteins was detected in HLA class I positive HNSCC (Fig. 3). CD8 positive T cells were also occasionally observed.

Humoral immune responses in cancer patients have been investigated broadly by ELISA against recombinant CT antigen proteins. The frequency of antibody responses

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Figure 4 Antibody response in cancer patients against CCDC62-2 and GKAP1 proteins by ELISA.

to MAGE was shown to be low in these patients[7,45]. In contrast, the anti-NY-ESO-1 antibody has been detected in many cancer types, including melanoma, lung, ovarian, breast, and bladder cancer. Approximately 7% of bladder cancer patients and 4% of esophageal cancer patients in Japan showed NY-ESO-1 antibody responses [66,67]. The frequency of anti-NY-ESO-1 antibody responses in patients with advanced NY-ESO-1 positive tumors has been estimated to be in the range of 25—50%, and the titer of the antibody appears to increase with progressive disease and decrease upon removal of the tumor or tumor regression [68]. The occurrence of CD4 and CD8 T-cell responses in NY-ESO-1 antibody-positive patients demonstrated the strong cellular immunogenicity of the NY-ESO-1 antigen. An integrated immune response including the antibody and CD4 and CD8 T-cell responses was repeatedly shown in patients with

NY-ESO-1-expressing tumors[46,47,69]. As potential cancer vaccine targets, the confirmation of immunogenicity in the human host is considered crucial for CT antigens. Only a few CT antigens have so far been shown to elicit coordinated humoral- and cell-mediated responses. T-cell responses to CT antigens are typically examined by screening overlapping peptide panels with CD8 or CD4 T-cells from human periph-eral blood mononuclear cell (PBMC). Many HLA-restricted T-cell epitopes have been identified this way, particularly for MAGE-A, NY-ESO-1, and SSX genes, and has formed the basis for peptide-based CT cancer vaccine trials and the monitoring of post-vaccination T-cell responses (http://www.cancerimmunity.org/peptidedatabase/ Tcellepitopes.htm).

Therefore, the immunogenicity of 2 novel CT antigens, CCDC62-2 and GKAP1, against HNSCC patients was analyzed by examining serum reactivity with ELISA using recombi-nant proteins. A total of 3/18 and 2/18 serum samples from HSNCC patients were reactive against CCDC62-2 and GKAP1, respectively (Fig. 4). None of the healthy donor serum was reactive. Three serum samples from the same panel of sera were also reactive against TEKT5[32]. Taken together, these findings suggest that the serologically-defined CT antigens, CCDC62-2, GKAP1, and TEKT5, may provide a molecu-lar basis for diagnostic and immunotherapeutic targets in HNSCC patients.

6. Conclusion

Immunotherapy includes both non-specific immunomodula-tion as well as cell-mediated immunotherapy and related treatment strategies that have the development of antigen-specific CD4 and CD8 T cell responses as their goal. Various immunotherapeutic approaches have been assessed clini-cally, but have had limited success, especially in HNSCC. Over the last decade, the importance of regulatory T cells and other mechanisms that limit a wide variety of physiolog-ical and pathologphysiolog-ical immune responses to tumor antigens and peptides has become clear. New strategies are cur-rently being developed to overcome these obstacles in order to develop effective cell-mediated immunotherapy. Recent progresses in tumor immunology based on the molecular identification of tumor antigens may allow immunotherapy to become another promising treatment to improve the out-comes of cancer patients. Following the introduction of the T cell epitope cloning technique by Boon et al., numerous antigens coding for immunogenic sequences have been iden-tified in different tumor types, including MAGE families in malignant melanoma and NY-ESO-1 in esophageal cancer. Cancer/testis (CT) antigens have become promising targets for the diagnosis of and immunotherapy for patients with various tumors because of their unique expression patterns. Serologically-defined novel CT antigens such as CCDC62-2, GKAP1, and TEKT5 were shown to be immunogenic in HNSCC patients, and this finding may provide provided a molecu-lar basis for diagnostic and immunotherapeutic targets in HNSCC patients.

Conflict or interest

None declared.

Acknowledgements

We thank Dr. Eiichi Nakayama at the Faculty of Health and Welfare, Kawasaki University of Medical Welfare for his continuous support during this study. This work was supported in part by a Grant-in Aid for Scientific Research

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Grant Numbers 21791997, 23792343 (S.D.) from the Japan Society for the Promotion of Science.

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