Humoral immune responses against cancer-testis antigens in human malignancies

1. Introduction

Cancer-testis antigens (CTAs) are a class of cancer antigens with extensive expression in human cancers [1, 2] and relative absence from normal tissues. However, some studies have revealed exceptions for this expression profile [3]. As their expression is normally limited to an immune-privileged site (i.e. the testis), if they are expressed in other tissues, they might induce immune responses [4]. Many of CTAs have been recognized through identification of humoral immune responses or T-cell responses elicited in the body [5]. Due to the high sensitivity, repeatability and simplicity of the assay, the presence of humoral immune response against an antigen is regarded as a valuable biomarker in patients [5]. Some studies have showed associations between the presence of antibody against the XAGE1 CTA and better overall survival in cancer patients [6]. However, in ovarian cancer patients antibody responses against any of the MAGE family CTAs were associated with worse outcome [7]. Regardless of the association between these immune responses and patients’ outcome, such antibodies can be used as biomarkers for cancer detection and patients’ follow-up. For instance, antibodies against NY-ESO-1 were significantly decreased in gastric cancer patients without recurrence after surgery [8]. In the current review article, we summarized the information about the presence of antibodies against CTAs in different cancers.

2. Humoral immune responses against CTAs in breast cancer

Dianatpour et al. have assessed antibody responses against three CTAs in breast cancer patients’ sera and detected antibodies against TSGA10 in 14% of patients. However, none of patients had anti TEX101 or anti ODF3 [9]. On the whole, based on the detection of autoantibodies against CTAs in breast cancer patients, these antigens have been used in clinical trials as therapeutic targets [10]. Several other CTAs such as FBXO39 [11], RHOXF2 and ODF4 [12] have been shown to be present in breast cancer cells but data regarding the presence of antibodies against them is not available. Ademuyiwa et al. have reported antibody responses against NY-ESO-1 in 73% of triple negative breast cancer (TNBC) patients whose tumors expressed this CTA. Such humoral responses were associated with higher numbers of CD8 positive cells [13]. Hamai et al. have suggested that the existence of humoral responses against NY-ESO-1 pinpoints a tumor subtype of hormone receptor negative breast cancer patients who would benefit from immunotherapy [14]. Stokert et al. have detected anti-NY-ESO-1 antibodies in 7.7% of breast cancer patients [15].

3. Humoral immune responses against CTAs in ovarian cancer

NY-ESO-1 and LAGE-1 have been expressed in a high number of epithelial ovarian cancer samples. Humoral immune responses against NY-ESO-1/LAGE-1 were detected in about one third of patients whose tumors were positive for these CTAs. Measurable antibodies were detected up to 3 years following primary diagnosis. However, no significant association was found between expression of these CTAs and patients’ outcome [16]. Another study in ovarian cancer patients detected NY-ESO-1 antibodies in 12.5% of patients [15].

4. Humoral immune responses against CTAs in prostate cancer

Several CTAs have been expressed in prostate cancer samples [17] among them are ODF1, ODF2, LEMD1 and SPATA19 [18]. Boehmer et al. have shown extensive expression of CTAs in late stage prostate cancers. However, MAGE-C2 was expressed in early stages, commonly stimulating MAGE-C2-targeted humoral responses. In high stage metastatic cases NY-ESO-1 is more commonly expressed and stimulates production of humoral responses [19]. Humoral immune responses against CTSP-1 have been identified in one fourth of prostate cancer patients. The presence of these antibodies was correlated with CTSP-1 protein expression but not the pathological parameters. The induction of humoral responses against CTSP-1 was considerably associated with a better outcome in patients with higher Gleason score [20].

5. Humoral immune responses against CTAs in skin cancers

CTAs have firstly identified in melanoma based on the presence of humoral responses [21]. Further studies revealed their expression in non-melanoma skin cancers as well [22]. Ghafouri-Fard et al. have reported expression of TEX101 and SPATA19 in basal cell carcinoma samples, but they did not assess their capacity in induction of immune responses in these patients [23]. A recent study in melanoma patients has shown strong humoral responses against MAGEA4 and MAGEA10 in about 8% of patients. The greatest frequency of robust responses was identified among stage II patients [24]. Another study has detected humoral response against NY-ESO-1 in 9.4% of melanoma patients all of them expressed this CTA in their tumors [15].

6. Humoral immune responses against CTAs in bladder cancer

Expression of several CTAs have been demonstrated in bladder cancer samples in a way that they constitute an important group of biomarkers in this kind of cancer [25]. Examples of over-expressed CTAs are KIF2B, CST8, TMEM225, RBM46 and OAZ3 [26]. Besides, assessment of CTAs expression in urinary exosomes has shown distinct patterns between bladder cancer patients and some non-malignant urological diseases which might indicate their suitability for immunotherapeutic interventions [27]. A survey about NY-ESO-1 expression in different cancer types including bladder cancer has shown decrease in the antibody levels against this CTA after curative removal of the primary bladder tumor [28].

7. Humoral immune responses against CTAs in brain cancer

Studies in glioblastoma samples have shown expression of several CTAs in adult patients [29] as well as children [30]. However, data regarding their potential to elicit humoral immune responses are scarce. Antibodies against PASD1 and FAM46D have been detected in a small percentage of glioblastoma patients [31].

8. Humoral immune responses against CTAs in liver cancer

ELISA-based techniques have shown the presence of antibodies against CTAs in sera of liver cancer patients [32]. Several CTAs have elicited humoral responses in these patients. Examples include CCDC110 [33], FATE1 [34], IMP3 [35], TSPY1 [36], NY-ESO-1 [37], PLAC1 [38], TSGA10 [39] and ZNF 165 [40]. However, for each CTA only a small fraction of patients had spontaneous immune responses.

9. Humoral immune responses against CTAs in hematologic cancers

TEX101 has been shown to be up-regulated in CML patients. However, antibodies against this CTA has been not detected in any of assessed patients [41]. In multiple myeloma patients, several CTAs have been shown to elicit immune responses [42]. In adult T cell leukemia, humoral immune responses, principally against NY-ESO-1, have been recognized in 11.6% of patients [43]. Antibodies against at least 1 CTA have been detected in 16.5% of non-Hodgkin’s lymphoma sera. High antibody levels against CT45 were detected in two diffuse large B-cell lymphoma cases [44]. Although CT7 has been recognized as the most common CTA in plasma cells of patients with light-chain (AL) amyloidosis, antibodies against this CTA was not detected in sera of patients. However, humoral responses against other CTAs have been occasionally detected in these patients [45].

10. Discussion

Although the presence of antibody responses against CTAs imply recognition of these antigens by the immune system and is regarded as a marker of prognosis in patients [46], the presence of these antigens on normal stem cells complicates the situation as these antibodies might interfere with the normal function of these antigens in stem cells [30]. The most potent immune responses against CTAs have been reported for NY-ESO-1 and MAGE-A3 antigens, so these antigens have been vastly used in clinical trials [47, 48]. For many other CTAs, there is no data about their capacity to induce immune response.

Notably, some strains of bacteria which are present as normal flora of different parts of the body regulate expression of CTAs [49]. Consequently, these bacteria might affect the presence of immune responses against CTAs as well as the clinical response to CTA-targeted therapies. Moreover, the presence of different splice variants for some CTAs [41] might affect the diversity of immunological responses in different patients. Based on the possible roles of CTAs in the detection of cancer and clues regarding the associations between immune responses against CTAs and patients’ outcome, further studies should assess the clinical importance of humoral immune responses against CTAs. The feasibility of ELISA-based methods for detection of these antibodies in sera of patients makes this approach practical.