Malignant mesothelioma-associated antigens recognized by tumor-infiltrating B cells and the clinical significance of the antibody titers

Our plain-English summary of Malignant mesothelioma-associated antigens recognized by tumor-infiltrating B cells and the clinical significance of the antibody titers, by Y. Shigematsu, T. Hanagiri, K. Kuroda, et al (Cancer Science, 2009).

The study

• Authors: Y. Shigematsu, T. Hanagiri, K. Kuroda, T. Baba, M. Mizukami, Y. Ichiki, M. Yasuda, M. Takenoyama, K. Sugio, K. Yasumoto
• Journal: Cancer Science
• Published: 2009;100(7):1326-34
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is difficult to diagnose at an early stage. The present study attempted to obtain a tumor-specific antibody against MPM derived from tumor-infiltrating B lymphocytes in MPM by using a xenotransplanted severe combined immunodeficiency (SCID) mouse model, and to identify the antigens recognized by the antibodies. Among the antigen-antibody relationships, the clinical usefulness of antibody titers in the sera was evaluated from the viewpoint of diagnosis of MPM and monitoring of therapeutic effects. Tumor tissue specimens from two patients with MPM were engrafted subcutaneously in SCID mice and blood samples were obtained and pooled every 2 weeks after xenotransplantation until 14 weeks when the mice were killed. A cDNA library was constructed from the mRNA of a MPM cell line (K921MSO). Immunoscreening of the libraries was carried out by serological identification of antigens by a recombinant expression cloning method (SEREX) and four antigens were identified as MPM-associated antigens. Among them, antibody titers against two antigens, Gene-X and thrombospondin-2 (THBS-2), were analyzed by phage plaque assay as the first step. ELISA systems correlated with the phage plaque assay to detect antibody titers against the two antigens were constructed using 20-mer peptides of the antigen-coding genes. The cut-off value was decided by the average and standard deviation of normal healthy persons. Antibody against Gene-X was detected in 10 out of 18 (55.6%) mesothelioma patients and antibody against THBS-2 was detected in 16 out of 18 (88.9%) mesothelioma patients. No patients with lung cancer regardless of asbestos exposure exhibited positive antibody titer against the two antigens. Furthermore, the serum antibody titers decreased after surgical treatment of MPM and increased after recurrence of the disease. The titers of the antibodies against Gene-X and THBS-2 could be used as tumor markers for the diagnosis and follow up of patients with MPM.

In plain English

This Japanese laboratory study sought blood markers of malignant pleural mesothelioma. The authors grafted tumor tissue from two mesothelioma patients under the skin of immune-deficient (SCID) mice. They used the human antibodies made by B cells inside the tumors to find the antigens those antibodies recognized. Four antigen-coding genes were identified: Gene-X, thrombospondin-2 (THBS-2, from a second reading frame beyond the gene's registered coding sequence), STUB-1 and IFT-88. The authors built blood tests for antibodies against Gene-X and THBS-2, setting cut-off levels from 25 healthy volunteers. Antibody to Gene-X was positive in 10 of 18 mesothelioma patients and 0 of 25 healthy donors. Antibody to THBS-2 was positive in 16 of 18 mesothelioma patients and 2 of 25 healthy donors. All 47 lung cancer patients, 27 of whom had a history of workplace asbestos exposure, and all 16 breast cancer patients tested negative for both. In two patients, antibody levels fell 2 to 4 months after surgery, and THBS-2 antibody levels rose when the disease returned. The authors concluded that these antibody levels could be used as tumor markers for diagnosing malignant mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory biomarker study: tumor grafts in SCID mice used to identify antigens, followed by blood antibody testing in patients and controls
• Who was studied: 18 patients with malignant pleural mesothelioma treated at the authors' hospital (University of Occupational and Environmental Health, Kitakyushu, Japan): 17 men and 1 woman, average age 65.9 years (range 54 to 82). Tumor tissue from two of them (M1 and M2) was grafted into SCID mice. Comparison groups were 47 lung cancer patients, 16 breast cancer patients and 25 healthy volunteers aged 26 to 44. Study dates are not given.
• Exposure: Not a study of asbestos exposure. The only exposure information given is that, of the 47 lung cancer patients, 27 had a history of workplace asbestos exposure and 20 did not. No fiber types or doses are reported.
• Main results:
  • Screening a gene library with antibodies from the mice grafted with mesothelioma tissue identified four antibody-reactive gene clones, matching Gene-X, THBS-2, STUB-1 and IFT-88.
  • The THBS-2 antigen came from a second reading frame (4506 to 4719 bp) downstream of the registered THBS-2 coding sequence (249 to 3767 bp).
  • By the first test (phage plaque assay), antibodies were found most often against Gene-X (13/18 mesothelioma patients, 0/25 healthy donors) and THBS-2 (17/18 mesothelioma patients, 2/25 healthy donors). STUB-1 antibodies were found in 1/18 patients and 0/25 donors; IFT-88 antibodies in 1/18 patients and 2/25 donors.
  • The ELISA cut-off was set at the healthy persons' average plus two standard deviations: 0.414 for the Gene-X peptide (positions 40 to 59) and 0.079 for the THBS-2 peptide (positions 26 to 45).
  • By ELISA, antibody against Gene-X was positive in 10 of 18 (55.6%) mesothelioma patients and 0 of 25 (0%) healthy donors.
  • By ELISA, antibody against the THBS-2 peptide (positions 26 to 45) was positive in 16 of 18 (88.9%) mesothelioma patients and 2 of 25 (8.0%) healthy donors.
  • All 47 lung cancer patients (with or without asbestos exposure) and all 16 breast cancer patients were negative for both antibodies.
  • In two operated patients (M15 and M18), antibody titers against both antigens fell 2 to 4 months after surgery. The disease returned at 10 and 9 months, and the THBS-2 antibody titers rose at the time of recurrence.
  • In tumor tissue, Gene-X was expressed in 3 of 9 mesothelioma tissues at more than 15.7-fold the level in normal testis, the highest-expressing normal tissue. THBS-2 was expressed in 7 of 9 at more than 10.1-fold the level in normal heart, the highest-expressing normal tissue.
• The authors' conclusion: The authors concluded that B cells inside mesothelioma tumors make antibodies against tumor-associated antigens, and that antibody titers against Gene-X and THBS-2 could be used as tumor markers for diagnosing malignant mesothelioma. They also suggested these titers could help evaluate the outcome of therapy.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Pleural Mesothelioma, Mesothelioma, Lung Cancer, Asbestos Exposure, Tumor Marker.

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