Ratio of intratumoral macrophage phenotypes is a prognostic factor in epithelioid malignant pleural mesothelioma

Our plain-English summary of Ratio of intratumoral macrophage phenotypes is a prognostic factor in epithelioid malignant pleural mesothelioma, by R. Cornelissen, L.A. Lievense, A.P. Maat, et al (PloS One, 2014).

The study

• Authors: R. Cornelissen, L.A. Lievense, A.P. Maat, R.W. Hendriks, H.C. Hoogsteden, A.J. Bogers, J.P. Hegmans, J.G. Aerts
• Journal: PloS One
• Published: 2014;9(9):e106742
• Cited by: 79 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Hypothesis: The tumor micro-environment and especially the different macrophage phenotypes appear to be of great influence on the behavior of multiple tumor types. M1 skewed macrophages possess anti-tumoral capacities, while the M2 polarized macrophages have pro-tumoral capacities. We analyzed if the macrophage count and the M2 to total macrophage ratio is a discriminative marker for outcome after surgery in malignant pleural mesothelioma (MPM) and studied the prognostic value of these immunological cells.

Methods: 8 MPM patients who received induction chemotherapy and surgical treatment were matched on age, sex, tumor histology, TNM stage and EORTC score with 8 patients who received chemotherapy only. CD8 positive T-cells and the total macrophage count, using the CD68 pan-macrophage marker, and CD163 positive M2 macrophage count were determined in tumor specimens prior to treatment.

Results: The number of CD68 and CD163 cells was comparable between the surgery and the non-surgery group, and was not related to overall survival (OS) in both the surgery and non-surgery group. However, the CD163/CD68 ratio did correlate with OS in both in the total patient group (Pearson r -0.72, p<0.05). No correlation between the number of CD8 cells and prognosis was found.

Conclusions: The total number of macrophages in tumor tissue did not correlate with OS in both groups, however, the CD163/CD68 ratio correlates with OS in the total patient group. Our data revealed that the CD163/CD68 ratio is a potential prognostic marker in epithelioid mesothelioma patients independent of treatment but cannot be used as a predictive marker for outcome after surgery.

In plain English

This study counted immune cells in tumor samples from 16 patients with epithelioid malignant pleural mesothelioma at Erasmus MC, Rotterdam. Eight had chemotherapy, then extended pleurectomy/decortication surgery, in a 2008-2010 clinical trial. Eight others, treated with chemotherapy only, were matched to them from 89 such patients treated during the course of the trial. In pre-treatment tumor samples, the authors counted CD8 T-cells, all macrophages (CD68) and M2-type macrophages (CD163). Counts were similar in the two groups. Neither the total macrophage count nor the CD8 count was related to overall survival. A higher share of M2 macrophages among all macrophages (the CD163/CD68 ratio) went with shorter survival in all 16 patients combined (Pearson r -0.72, p less than 0.05). In the surgery group alone this was only a trend that was not statistically significant. In laboratory tests, fluid from six mesothelioma cell lines shifted macrophages toward an M2-like type to varying degrees. The authors concluded the ratio is a possible prognostic marker but does not predict outcome after surgery. They noted the small number of patients. Asbestos exposure was not studied.

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: Small matched comparison of tumor tissue from patients treated with surgery after chemotherapy vs chemotherapy only, using immunohistochemistry and correlation with overall survival, plus an in vitro (laboratory) macrophage experiment
• Who was studied: 16 patients with epithelioid malignant pleural mesothelioma at Erasmus MC Cancer Institute, Rotterdam, the Netherlands. 8 had extended pleurectomy/decortication after induction chemotherapy during a clinical trial between 2008 and 2010. 8 had chemotherapy only and were selected out of 89 patients treated only with chemotherapy during the course of the trial, because adequate tissue was not available for all patients in the trial's best supportive care arm. There were 12 men and 4 women, with a median age of 62 (range 36-75).
• Exposure: Not asbestos exposure. The study measured numbers of CD8 T-cells, CD68 (all) macrophages and CD163 (M2) macrophages in pre-treatment tumor specimens. Treatment was 4 cycles of pemetrexed with cisplatin or carboplatin, with or without pleurectomy/decortication 8 to 10 weeks after chemotherapy.
• Main results:
  • CD68 (total macrophage) counts were similar between the surgery and non-surgery groups: mean 211.3 (SD 80.2) vs mean 213.9 (SD 100.4), p = 1.0
  • CD163 (M2 macrophage) counts were similar between the surgery and non-surgery groups: mean 168.3 (SD 80.2) vs mean 164.1 (SD 82.5), p = 0.8
  • In all patients, the CD68 count did not correlate with overall survival (Pearson r -0.07, p = 0.81). The CD163 count showed an inverse trend that was not statistically significant (Pearson r -0.33, p = 0.22).
  • The CD163/CD68 ratio was significantly negatively correlated with overall survival in the total group of 16 patients (Pearson r -0.72, p less than 0.05)
  • By group: in the non-surgery group the correlation was significant (Pearson r -0.91, p = 0.001). In the surgery group there was only a trend (Pearson r -0.65, p = 0.08).
  • CD8 counts were comparable between groups (p = 0.51). CD8 counts were not correlated with overall survival in the surgery group (p = 0.88), the non-surgery group (p = 0.96) or the whole group (p = 0.73).
  • In laboratory cultures, conditioned media from six mesothelioma cell lines shifted macrophages toward an M2 phenotype to varying degrees
• The authors' conclusion: The authors concluded that the CD163/CD68 ratio was a prognostic marker in a limited number of epithelioid mesothelioma patients, but not a predictive marker for outcome after surgery
• Limitations the authors state:
  • The number of patients was small
  • The underlying trial was stopped because of slow accrual
  • Only patients with the epithelioid subtype were selected for surgery
  • The trend in the surgery group needs confirmation in a larger patient group
  • No definitive M1 macrophage marker was available, so a true M1/M2 ratio could not be measured
  • Failure to reproduce earlier CD8 findings could be due to the small number of surgical patients

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: Macrophage, Epithelioid, Pleural Mesothelioma, Chemotherapy, Histology, Overall Survival, Prognosis, Mesothelioma.

Related studies

• Intratumoral macrophage phenotype and CD8+ T lymphocytes as potential tools to predict local tumor outgrowth at the intervention site in malignant pleural mesothelioma — R. Cornelissen, L.A. Lievense, et al. (2015)
• Prognostic Significance of B7-H3 Expression and CD163+ Tumor-Associated Macrophage Infiltration in Mesothelioma — T. Koç, R.O. Yüceer, et al. (2026)
• Zoledronic acid impairs myeloid differentiation to tumour-associated macrophages in mesothelioma — J.D. Veltman, M.E. Lambers, et al. (2010)
• NOX4 modulates macrophage phenotype and mitochondrial biogenesis in asbestosis — C. He, J.L. Larson-Casey, et al. (2019)
• Pleural Effusion of Patients with Malignant Mesothelioma Induces Macrophage-Mediated T Cell Suppression — L.A. Lievense, R. Cornelissen, et al. (2016)
• Tumor-associated macrophages in thoracic malignancies — L.A. Lievense, K. Bezemer, et al. (2013)

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