Clinical significance of cancer/testis antigens expression in patients with non-small cell lung cancer

Abstract

Cancer/testis antigens (CT antigens) are thought to be suitable targets for antigen-specific immunotherapy, because of the cancer-specific expression except for the testis among various normal tissues and no-expression of HLA class I in the testis. In the present study, the expressions of CT antigens (MAGE-A3, MAGE-A4, NY-ESO-1 and KK-LC-1) in non-small cell lung cancer (NSCLC) were analyzed by RT-PCR. The subjects were 239 patients with NSCLC who underwent surgery from 2001 to 2005 in our department. The expression rates of MAGE-A3, MAGE-A4, NY-ESO-1 and KK-LC-1 were 23.8%, 20.1%, 10.5% and 32.6% in patients with NSCLC, respectively. MAGE-A4 was expressed more frequently in male (25.3%) than in female (10.6%) (p < 0.01). The positive proportion of MAGE-A4 was higher in stages II–IV (30.6%) than in stage I (12.8%) (p < 0.01). Both of MAGE-A3 and MAGE-A4 were expressed more frequently in squamous cell carcinoma than in adenocarcinoma (p < 0.01). Such tendency was not observed among NY-ESO-1 and KK-LC-1 expression. KK-LC-1 was expressed in 32.1% of patients with adenocarcinoma and in 36.5% of patients with squamous cell carcinoma. Patients with positive MAGE-A4 expression showed significantly poorer overall survival than those without MAGE-A4 expression (p = 0.013), and such effect on survival was also observed, when the analysis was limited to patients at stage I (p = 0.0037). Expression of MAGE-A3, NY-ESO-1 or KK-LC-1 did not affect survival of patients with NSCLC significantly, however, expression of at least one of such CT antigens negatively affect survival of patients with NSCLC (p = 0.045).

Introduction

Lung cancer is the most common malignant neoplasm and the leading cause of cancer mortality in most industrialized country [1]. In spite of advances in diagnostic and therapeutic modalities against lung cancer, little improvement in prognostic outcome has been accomplished. Recent clinical studies suggested favorable effects of immunotherapy as one of the alternative treatment approaches for lung cancer [2], [3], [4]. A large number of tumor-associated antigens (TAAs) have been identified in various human cancers [5], [6], [7], [8], [9], [10], [11]. These antigens are classified into such categories as follows: cancer/testis (CT) antigens, differentiation antigens, amplification or overexpression antigens, tumor-specific mutated antigens and antigens derived from oncogenic viruses. Suitable conditions as cancer antigens for immunotherapy would be specific and stable expression by tumors, no expression in normal tissues and having crucial function for survival of cancer cells. CT antigens are expressed specifically in cancer cells except for testis among normal tissues. Moreover, the testis does not express HLA class I. Therefore, immunization against CT antigen may not elicit autoimmune disease. To date, over 50 CT antigens have been identified [12] since melanoma-associated antigen gene (MAGE)-A1 had been identified firstly as a tumor rejection antigen in 1991 [5]. BAGE, GAGE, NY-ESO-1 and SSX-2 have been identified at first in melanoma [5], [13], [14], [15], [16]. However, these CT antigens were expressed in not only melanoma but also such cancers from lung, breast, esophagus, stomach and colon. Furthermore, these CT antigen-proteins involve several epitope peptides recognized by CTLs in the content of specific types of HLA class I and those of HLA class II.

We previously reported a newly identified CT antigen from lung cancer designated as Kita-Kyushu Lung Cancer antigen-1 (KK-LC-1) [10]. KK-LC-1 was not expressed in normal tissues except for testis, and located on X chromosome (Xq 22). Recently, MAGE-A3 and NY-ESO-1 were applied for clinical trials of vaccine immunotherapy for cancer patients [4], [17]. We have now been planning to start MAGE-A4 immunotherapy against patients with NSCLC [18]. In the present study, we investigated frequencies of expression of such 4 cancer/testis antigens as MAGE-A3, MAGE-A4, NY-ESO-1 and KK-LC-1 in lung cancer, and significances of expression of CT antigens in clinical and pathological characteristics of lung cancer were evaluated.