Toward a more complete recognition of immunoreactive antigens in squamous cell lung carcinoma

Abstract

There is very limited knowledge about the antibody response against tumor-expressed antigens in lung cancer. To arrive at a more complete picture of lung cancer antigens, we generated 2 cDNA libraries from squamous cell lung carcinoma and isolated 15 immunogenic antigens using autologous sera. Among the antigens most frequently identified were the lymphoid blast crisis oncogene (LBC), an unknown hypothetical protein and the p53-binding protein (TP53 BP), which have already been associated with tumor development. Of the immunogenic antigens, 6 map to chromosomes that are frequently altered in squamous cell lung carcinoma. SEREX database analysis showed that 7 of the identified immunogenic antigens have been associated with the humoral immune response in other human tumors. Screening with heterologous sera of patients with lung carcinoma identified 4 antigens, including human protein kinase C and TP53 BP, which have also been found by autologous screening. Only 1 of the 15 identified antigens reacted with any of the 36 control sera, which were taken from individuals without known disease. Sera from adenocarcinoma and large cell carcinoma of the lung were not reactive for the antigens. In summary, using 2 newly established cDNA libraries, we isolated 15 novel antigens, which were subsequently evaluated for the frequency of their corresponding antibodies in autologous, normal and heterologous sera; their chromosomal localization; and their correlation with survival after surgery. © 2002 Wiley-Liss, Inc. Key words: lung cancer; SEREX; autologous sera; heterologous seraThere is mounting evidence that many tumors express antigens that elicit an immune response in cancer patients. Target antigens of tumor-related autoantibodies can be oncoproteins, tumor-suppressor proteins or proliferation-associated antigens. 1 The most prominent example of an autoimmune response against a tumorassociated protein is the antibody response against the tumorsuppressor TP53. Examples of TP53-directed antibodies in cancer patients include antibodies in 50% of bladder cancer patients, in 12% of B-cell lymphoma patients, in 23% of ovarian cancer patients, in 32% of colon cancer patients and in 42% of breast cancer patients. [2][3][4][5][6] In addition, there is an increasing number of other tumor or proliferation-associated gene products that cause an antibody response, including, e.g., c-myb with an antibody response in 43% of breast cancer patients and cyclin B1 in 15% of hepatocellular carcinoma patients. 7,8 There are limited data on the autoantibody response in human lung cancer patients, specifically patients suffering from squamous cell lung carcinoma, which constitutes 40 -50% of lung cancer patients. Lung cancer is the most frequent lethal tumor in Western societies, with a 5-year survival rate of approximately 13%. 9 The most frequent autoantibodies in lung cancer patients are directed against TP53, with an antibody response detected in 14.3% of lung cancer patients and 21% of small cell lung cancer patients, and against L-myc and ...

Tumor-associated Antigen Arrays for the Serological Diagnosis of Cancer

“…These autoantibodies have been detected in several human cancers, and significant advances have been made in the identification of their target antigens, particularly in lung cancer (28,30), colorectal cancer (36), breast cancer (29), prostate cancer (27,37), leukemia (26), non-Hodgkin lymphoma (24), hepatocellular carcinoma (25,32,34), ovarian cancer (31), pancreatic cancer (33,38), and paraneoplastic neurological syndromes (35). Although the mechanisms leading to autoantibody production in cancer patients are not clearly understood, emerging evidence indicates that most TAAs are cellular proteins whose aberrant regulation or function could be linked to malignancy (3).…”

“…A later variant of this approach, termed SEREX, used cDNA expression libraries that were constructed from a patient's tumors and screened with autologous sera (117,118). SEREX has been exploited by several groups for the identification of hundreds of candidate TAAs in various human cancer types (119), including but not limited to lung cancer (28), liver cancer (120), breast cancer (121), prostate cancer (122), ovarian cancer (123), renal cancer (124), head and neck cancer (125), esophageal cancer (126), lymphoma (127), and leukemia (89). Although a powerful approach for the identification of candidate TAAs, SEREX has several limitations.…”

Serologic Autoantibodies as Diagnostic Cancer Biomarkers—A Review

“…To counteract these mortality rates, research has focused on the development of diagnostic tools that enable the diagnosis of a cancer earlier before it progresses to an often incurable metastatic stage (5). Autoantibody levels in patient blood serum have been proposed as diagnostic biomarkers for early-stage diagnosis of cancers, as an increase in serum levels of certain autoantibodies has been shown to precede the development of disease symptoms (6, 7) and correlate with cancer incidence (8) for cancers of the breast (9), lung and small cell lung (10,11), colon (12), ovary (13), prostate (14), and head and neck cancer (15,16).…”

Immune responses to DNA mismatch repair enzymes hMSH2 and hPMS1 in patients with pancreatic cancer, dermatomyositis and polymyositis

“…[20][21][22] However, the particular p53 clone isolated in our study was recognized by sera from patients with a limited cancer including pancreatic cancer and was not recognized by sera from colon cancer patients. Downregulation of HMT1 which may upregulate antiproliferating effects of IFNs through interaction with the intracytoplasmic domain of the Type I interferon (IFN) receptor was reported in breast cancer.…”