CTLA-4 in mesothelioma patients: tissue expression, body fluid levels and possible relevance as a prognostic factor

Our plain-English summary of CTLA-4 in mesothelioma patients: tissue expression, body fluid levels and possible relevance as a prognostic factor, by S. Roncella, S. Laurent, V. Fontana, et al (Cancer Immunology, Immunotherapy, 2016).

The study

• Authors: S. Roncella, S. Laurent, V. Fontana, P. Ferro, M.C. Franceschini, S. Salvi, S. Varesano, S. Boccardo, A. Vigani, A. Morabito, P.A. Canessa, U. Giannoni, I. Rosenberg, A. Valentino, F. Fedeli, D.F. Merlo, M. Ceppi, S. Riggio, M. Romani, D. Saverino, A. Poggi, M.P. Pistillo
• Journal: Cancer Immunology, Immunotherapy
• Published: 2016;65(8):909-17
• Cited by: 40 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

CTLA-4 function as a negative regulator of T cell-mediated immune response is well established, whereas much less is known about the immunoregulatory role of its soluble isoform (sCTLA-4). No data are available on CTLA-4 expression and prognostic impact in malignant pleural mesothelioma (MPM). We investigated, by immunohistochemistry, CTLA-4 expression in tumor tissues and, by ELISA, sCTLA-4 levels in sera and matched pleural effusions from 45 MPM patients. Prognostic effect of CTLA-4 expression on overall survival (OS) was assessed through Cox regression and prognostic significance expressed as death rate ratio (HR). We found that 56.0 % of MPM tissues expressed CTLA-4 with variable intensity and percentage of positive cells estimated by the immunoreactive score. sCTLA-4 levels were significantly higher in sera (S-sCTLA-4) than in pleural effusions (PE-sCTLA-4) (geometric mean ratio = 2.70, P value = 0.020). CTLA-4 expression at the tissue level was higher in the epithelioid histological subtype than in the sarcomatoid, whereas at the serum level, it was higher in the sarcomatoid subtype. A homogeneous favorable prognostic effect was found for CTLA-4 overexpression in tissue, serum and pleural effusion. Interestingly, only the PE-sCTLA-4 was found to be a statistically significant positive prognostic factor (HR = 0.37, 95 % CI = 0.18-0.77, P value = 0.007). Indeed, PE-sCTLA-4 correlated with CTLA-4 expression in tissues, whereas this latter expression showed a weak association with OS. To confirm our findings, further experimental evidences obtained from a larger cohort of MPM patients are required. However, our results would indicate a positive correlation of PE-sCTLA-4 levels and OS in MPM patients.

In plain English

This Italian study measured CTLA-4, a protein that dampens immune T cells, in people with malignant pleural mesothelioma. It included 76 patients with fluid around the lung (pleural effusion) seen in Sarzana, La Spezia, between March 2008 and July 2011. Of these, 45 had mesothelioma and 31 had benign conditions, including asbestos-induced pleuritis. In the authors' table, 29 of the 45 mesothelioma patients were listed as asbestos-exposed. CTLA-4 was found in 23 of 41 tested tumor samples (56.0%). The soluble form was higher in blood than in pleural fluid in mesothelioma patients (geometric mean ratio 2.70, P value 0.020). It did not differ significantly between mesothelioma and benign patients. Mesothelioma patients with pleural-fluid levels above 67 pg/ml had a lower death rate than those at or below that level (hazard ratio 0.36, 95% CI 0.17 to 0.76, P value 0.007). Higher tumor and blood levels also went with lower death rates, but these results were not statistically significant. The authors concluded that CTLA-4 in pleural fluid might be a favorable prognostic factor. They said larger studies are needed and noted the small sample size.

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: Observational study of tumor tissue (immunohistochemistry) and matched serum and pleural fluid (ELISA), with survival analysis by Cox regression
• Who was studied: 76 patients with pleural effusion who underwent thoracentesis at the Division of Pneumology, Sarzana (La Spezia), Italy, March 2008 to July 2011. Of these, 45 had malignant pleural mesothelioma (93.3% male, median age 73.9) and 31 had benign pulmonary diseases, used as controls. Tumor tissue was available for 41 mesothelioma patients.
• Exposure: The factor studied was CTLA-4 (in tumor tissue, and its soluble form in serum and pleural fluid), not asbestos. Table 1 lists 29 of 45 mesothelioma patients (64.5%) as asbestos-exposed and 16 as unexposed. No fiber types are given.
• Main results:
  • CTLA-4 was found in 23 of 41 mesothelioma tumor tissues (56.0%), with variable proportion of positive cells and staining intensity.
  • In mesothelioma patients, soluble CTLA-4 was significantly higher in serum than in pleural fluid (geometric mean 71.3 vs 26.4 pg/ml; GM ratio 2.70, P value 0.020).
  • There were no statistically significant differences in serum or pleural-fluid soluble CTLA-4 levels between mesothelioma and benign-disease patients.
  • Compared with other subtypes, epithelioid tumors had fewer CTLA-4-negative tissues (38.5 vs 53.3%) and more with strong expression (30.8 vs 20.0%), but these differences were not statistically significant.
  • Serum soluble CTLA-4 in the sarcomatoid subtype was about three times the level in the epithelioid subtype (geometric mean 146.0 vs 46.9 pg/ml).
  • Among 38 male mesothelioma patients, those with CTLA-4-positive tumor tissue had a lower death rate than those with negative tissue, not statistically significant (HR 0.57; 95% CI 0.28 to 1.20).
  • Mesothelioma patients with serum soluble CTLA-4 above 66 pg/ml had a lower death rate than those at or below it, not statistically significant (HR 0.81; 95% CI 0.37 to 1.81).
  • Mesothelioma patients with pleural-fluid soluble CTLA-4 above 67 pg/ml had about a 60% lower death rate than those at or below it (HR 0.36; 95% CI 0.17 to 0.76; P value 0.007).
  • Median overall survival for all mesothelioma patients was 12.7 months (95% CI 8.5 to 14.8), with median follow-up 11.8 months.
  • In 38 patients with all three samples, CTLA-4-positive tumors had higher serum (52.8 vs 15.0) and pleural-fluid (30.9 vs 17.8) geometric mean levels than negative tumors, but the differences were not statistically significant.
• The authors' conclusion: The authors concluded that CTLA-4 over-expression in pleural fluid might be a favorable prognostic factor for overall survival in mesothelioma patients. They said this needs confirming in larger samples.
• Limitations the authors state:
  • Small sample size, which the authors suggest is probably why only the pleural-fluid result reached statistical significance; larger studies are needed to confirm the findings.
  • The tumor-tissue survival analysis was limited to men because only two women had a valid score.

Topics

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

Medical terms in this study, explained in our Lexicon: CTLA-4, Mesothelioma, Pleural Mesothelioma, Immunohistochemistry, Pleural Effusion, Overall Survival, rate ratio, Epithelioid.

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