Serologic responses in patients with malignant mesothelioma: evidence for both public and private specificities

Our plain-English summary of Serologic responses in patients with malignant mesothelioma: evidence for both public and private specificities, by C. Robinson, M. Callow, S. Stevenson, et al (American Journal of Respiratory Cell and Molecular Biology, 2000).

The study

• Authors: C. Robinson, M. Callow, S. Stevenson, B. Scott, B.W. Robinson, R.A. Lake
• Journal: American Journal of Respiratory Cell and Molecular Biology
• Published: 2000;22(5):550-6
• Cited by: 36 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma (MM) is a pulmonary malignancy that appears to be immunogenic based on a large number of studies in both animals and humans. This notion is supported by our recent demonstration using Western blot analysis of immunoglobulin G antibodies reactive with a variety of autoantigens in many patients with MM. In view of the enormous potential of such antigens in early diagnosis, immunotherapy, and vaccination of at-risk individuals, it was essential to identify these antigens. We therefore applied the SEREX technique (serologic identification by recombinant expression cloning), using a serum pool from six patients as the probe against an expressed complementary DNA library derived from a cloned MM cell line. We screened over one million recombinants and obtained sequence information on eight antigens that had provoked immunoglobulin heavy chain class switching, presumably as a consequence of T-cell recognition. Six of these antigens were identifiable (U2AF[65], Siah binding protein, topoisomerase IIbeta, ZFM1, mIre1, and pendulin), and of the others, one was found as a single EST from a myotube library (Jemm-1); the other (Jemm-2) was not represented in any EST database even as a weak homolog. Consistent with our previous findings, each of the characterizable antigens would be expected to be associated with the cell nucleus. Each of the autoantibody specificities was uniquely associated with a single patient with the exception of antibodies to TOPIIbeta and U2AF(65). We found 13 of 14 (93%) patients with MM had antibodies to TOPIIbeta and two of 14 (14%) patients had antibodies to U2AF(65). The number of serum reactivities, taken as a measure of the complexity of the immune response, correlates with patient survival and with an index of systemic inflammation. These data suggest that a broader range of serologic reactivities reflects a more active host response to the presence of tumor.

In plain English

This laboratory study, from Perth, Western Australia, looked for proteins that trigger antibodies in the blood of people with malignant mesothelioma. The authors pooled serum from six patients and used it to screen a gene library made from a mouse mesothelioma cell line (AB1). That cell line had been derived from mice injected in the abdomen with crocidolite asbestos. They identified eight proteins. They then tested serum from 14 patients (13 men, one woman, aged 40 to 81) and 16 healthy laboratory volunteers against each protein. Antibodies to topoisomerase II beta were found in 13 of 14 patients and in 6 of 16 volunteers, though the volunteers' reactions were generally weak. Antibodies to U2AF(65) were found in two patients. Each other protein was recognized by one patient and by no volunteers. Patients with two or more reactivities had longer average survival from diagnosis (29 months, versus 10.5 months with none) and a higher sedimentation rate, a blood marker of inflammation. Reactivity was not linked to tumor size. The authors concluded these reactivities might ultimately help diagnosis. They noted that the survival link was hard to assess and that scoring was subjective.

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 study of antibodies in patient blood (serum), using the SEREX technique (screening a gene expression library with patient serum), plus testing of individual patient and control sera against the antigens found
• Who was studied: 14 patients with malignant mesothelioma (13 men and one woman, aged 40 to 81) attending the respiratory clinic at the Queen Elizabeth II Medical Centre, Perth, Western Australia. The comparison group was 16 healthy laboratory volunteers aged 29 to 58. Serum from six of the patients was pooled for the library screen.
• Exposure: The article does not describe the patients' own asbestos exposure. The gene library was built from a mouse mesothelioma cell line (AB1) that was derived from mice injected intraperitoneally (into the abdomen) with crocidolite asbestos.
• Main results:
  • Screening identified eight different antigens: U2AF(65), Siah binding protein, topoisomerase II beta, ZFM1, mIre1, pendulin, and two previously undescribed transcripts named Jemm-1 and Jemm-2.
  • Antibodies to topoisomerase II beta were found in 13 of 14 (93%) patients with malignant mesothelioma and in 6 of 16 (37%) healthy laboratory volunteers.
  • The volunteers' positive reactions to topoisomerase II beta were generally only weakly positive on the subjective scoring. Some patients were strongly positive.
  • Antibodies to U2AF(65) were found in 2 of 14 patients. Each of the other six antigens was recognized by a single patient. No control subject was positive for any of these antigens.
  • Survival from diagnosis to death was longest in patients with more than one serum reactivity. By group (Table 2): no reactivities (n = 4), 10.5 months; topoisomerase II only (n = 5), 20.8 months, with one patient still alive at the time of analysis; two or more reactivities (n = 4), 29 months.
  • Patients with two or more reactivities had a higher erythrocyte sedimentation rate (65 mm/h) than those with no reactivities (29 mm/h) or topoisomerase II only (31 mm/h).
  • The number of serum reactivities was not correlated with tumor bulk measured on chest CT.
  • None of the antigens found was expressed only in mesothelioma.
• The authors' conclusion: The authors concluded that patients with malignant mesothelioma show antibody reactivity to proteins made by mesothelioma cells. Some reactivities are shared among patients (public) and some are unique to one patient (private). They said these might ultimately be useful in diagnosis. They suggested that a broader range of reactivities reflects a more active host response to the tumor.
• Limitations the authors state:
  • The meaning of the link between a broader antibody response and survival was difficult to assess because few serially collected serum samples were available.
  • The authors raised an alternative explanation for the survival link: patients who live longer may simply have more time to mount an immune response. They considered this less likely.
  • Antibody scoring was subjective. Meaningful scores could not be obtained because each filter had a different background. A quantitative assay was still needed.
  • Using a mouse rather than a human gene library may have lowered the sensitivity of the screen.
  • The authors could not measure how strongly these genes were expressed in the patients' own primary tumors.

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Immunotherapy, Inflammation.

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