Prognostic Role of Tumor Immune Microenvironment in Pleural Epithelioid Mesothelioma

Our plain-English summary of Prognostic Role of Tumor Immune Microenvironment in Pleural Epithelioid Mesothelioma, by H. Ollila, M.I. Mäyränpää, L. Paavolainen, et al (Frontiers in Oncology, 2022).

The study

• Authors: H. Ollila, M.I. Mäyränpää, L. Paavolainen, J. Paajanen, K. Välimäki, E. Sutinen, H. Wolff, J. Räsänen, O. Kallioniemi, M. Myllärniemi, I. Ilonen, T. Pellinen
• Journal: Frontiers in Oncology
• Published: 2022;12:870352
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Pleural mesothelioma (MPM) is an aggressive malignancy with an average patient survival of only 10 months. Interestingly, about 5%-10% of the patients survive remarkably longer. Prior studies have suggested that the tumor immune microenvironment (TIME) has potential prognostic value in MPM. We hypothesized that high-resolution single-cell spatial profiling of the TIME would make it possible to identify subpopulations of patients with long survival and identify immunophenotypes for the development of novel treatment strategies.

Methods: We used multiplexed fluorescence immunohistochemistry (mfIHC) and cell-based image analysis to define spatial TIME immunophenotypes in 69 patients with epithelioid MPM (20 patients surviving ≥ 36 months). Five mfIHC panels (altogether 21 antibodies) were used to classify tumor-associated stromal cells and different immune cell populations. Prognostic associations were evaluated using univariate and multivariable Cox regression, as well as combination risk models with area under receiver operating characteristic curve (AUROC) analyses.

Results: We observed that type M2 pro-tumorigenic macrophages (CD163+pSTAT1-HLA-DRA1-) were independently associated with shorter survival, whereas granzyme B+ cells and CD11c+ cells were independently associated with longer survival. CD11c+ cells were the only immunophenotype increasing the AUROC (from 0.67 to 0.84) when added to clinical factors (age, gender, clinical stage, and grade).

Conclusion: High-resolution, deep profiling of TIME in MPM defined subgroups associated with both poor (M2 macrophages) and favorable (granzyme B/CD11c positivity) patient survival. CD11c positivity stood out as the most potential prognostic cell subtype adding prediction power to the clinical factors. These findings help to understand the critical determinants of TIME for risk and therapeutic stratification purposes in MPM.

Copyright © 2022 Ollila, Mäyränpää, Paavolainen, Paajanen, Välimäki, Sutinen, Wolff, Räsänen, Kallioniemi, Myllärniemi, Ilonen and Pellinen.

In plain English

This Finnish study looked at immune cells in tumor tissue from 69 patients with epithelioid pleural mesothelioma diagnosed between 2000 and 2012. Twenty of them survived longer than 36 months. The samples were taken at diagnosis, before any treatment. They were stained with 21 antibodies, and computer image analysis measured each immune cell type as a percentage of all cells in the tissue around the tumor cells. The study did not examine asbestos exposure. The analysis took age, gender, disease stage and grade into account. In that analysis, more M2 macrophages were associated with shorter survival (hazard ratio 1.05, 95% confidence interval 1.01–1.10). More granzyme B-positive cells (0.29, 0.11–0.76) and more CD11c-positive cells (0.94, 0.90–0.99) were associated with longer survival. Adding CD11c-positive cells to the clinical factors raised a measure of prediction accuracy (AUROC) from 0.67 to 0.84. Markers targeted by immunotherapy, such as PD-1 and PD-L1, showed no association with survival. The authors concluded that these cell types may potentially help estimate prognosis. They said the findings need confirming in larger groups and may not apply to other mesothelioma tissue types.

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: Retrospective study of stored tumor tissue (tissue microarrays) linking immune cell counts to patient survival, using Cox regression and prediction-model (AUROC) analyses
• Who was studied: 69 Finnish patients with epithelioid pleural mesothelioma diagnosed between 2000 and 2012. Median age at diagnosis was 66 years and median survival was 19 months. 57 (83%) were male and 20 (29%) survived longer than 36 months. Five patients with biphasic histology were excluded. Tissue was taken at diagnosis, before treatment.
• Exposure: Asbestos exposure was not studied or reported. The factors examined were immune cell populations in the tissue around the tumor: T and B lymphocytes, NK cells, M1 and M2 macrophages, dendritic cells and others. These were measured with five staining panels using 21 antibodies. Each cell type was expressed as a percentage of all stromal cells and analyzed as a continuous value.
• Main results:
  • In unadjusted (univariate) analysis, M2 macrophages (CD163+pSTAT1−HLA-DRA1− cells) were associated with shorter survival: HR = 1.07, p = 0.002.
  • In univariate analysis, granzyme B+ cells (HR = 0.32, p = 0.005) and CD11c+ cells (HR = 0.94, p < 0.001) were associated with longer survival.
  • In univariate analysis, M1 macrophages were associated with longer survival (HR = 0.95, p = 0.033). After adjustment for age, gender, grade and stage, the association was not statistically significant (HR 0.94, 95% CI 0.87–1.01, p = 0.11).
  • In the combined multivariable model (n = 66), adjusted for age, gender, clinical stage and grade, M2 macrophages remained associated with shorter survival: HR 1.05 (95% CI 1.01–1.10), p = 0.02.
  • In the combined multivariable model, granzyme B+ cells remained associated with longer survival: HR 0.29 (95% CI 0.11–0.76), p = 0.01.
  • In the combined multivariable model, CD11c+ cells remained associated with longer survival: HR 0.94 (95% CI 0.90–0.99), p = 0.01.
  • CD11c+ cells were the only immune cell type that increased prediction accuracy when added to the clinical factors (age, gender, clinical stage, grade): AUROC rose from 0.67 to 0.84.
  • 97.1% of CD11c+ cells were negative for the monocyte marker CD16. The authors took this to suggest that the CD11c-associated effect comes largely from dendritic cells.
  • No associations with survival were observed for the checkpoint markers PD-1 and PD-L1 or the exhaustion markers TIM3, LAG3 and IDO.
• The authors' conclusion: The authors concluded that more M2 macrophages in the tumor stroma is an independent prognostic factor for shorter survival. More CD11c+ and granzyme B+ stromal cells are independent prognostic factors for longer survival. These cell types, especially CD11c-expressing dendritic cells, may potentially be used as prognostic factors, and further studies are warranted on whether they could guide immunotherapy.
• Limitations the authors state:
  • Because mesothelioma is rare, the findings need to be confirmed in larger independent cohorts.
  • Only patients with epithelioid histology were studied, so the results may not apply to other histological subtypes.
  • The Ki67 proliferation marker was excluded from the main analyses because positive cells could not be reliably assigned to tumor or immune cells.

Topics

Medical terms in this study, explained in our Lexicon: Epithelioid, Mesothelioma, Pleural Mesothelioma, Immunohistochemistry, Macrophage.

Related studies

• High tumor cell platelet-derived growth factor receptor beta expression is associated with shorter survival in malignant pleural epithelioid mesothelioma — H. Ollila, J. Paajanen, et al. (2021)
• Histopathological features of epithelioid malignant pleural mesotheliomas in patients with extended survival — J. Paajanen, S. Laaksonen, et al. (2020)
• Characterization of the immune microenvironment in malignant pleural mesothelioma reveals prognostic subgroups of patients — N. Fusco, V. Vaira, et al. (2020)
• Prognostic Implications of Pan-Cancer CMTM6 Expression and Its Relationship with the Immune Microenvironment — Y. Zhao, M. Zhang, et al. (2020)
• Priming the tumor immune microenvironment with chemo(radio)therapy: A systematic review across tumor types — T. van den Ende, H.G. van den Boorn, et al. (2020)
• Molecular and Histopathological Characterization of the Tumor Immune Microenvironment in Advanced Stage of Malignant Pleural Mesothelioma — N.S. Patil, L. Righi, et al. (2018)

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