Complex Immune Contextures Characterise Malignant Peritoneal Mesothelioma: Loss of Adaptive Immunological Signature in the More Aggressive Histological Types

Our plain-English summary of Complex Immune Contextures Characterise Malignant Peritoneal Mesothelioma: Loss of Adaptive Immunological Signature in the More Aggressive Histological Types, by M. Tazzari, S. Brich, A. Tuccitto, et al (Journal of Immunology Research, 2018).

The study

• Authors: M. Tazzari, S. Brich, A. Tuccitto, F. Bozzi, V. Beretta, R.D. Spagnuolo, T. Negri, S. Stacchiotti, M. Deraco, D. Baratti, C. Camisaschi, A. Villa, B. Vergani, L. Rivoltini, S. Pilotti, C. Castelli
• Journal: Journal of Immunology Research
• Published: 2018;2018:5804230
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant peritoneal mesothelioma (MpM), arising in the setting of local inflammation, is a rare aggressive tumour with a poor prognosis and limited therapeutic options. The three major MpM histological variants, epithelioid (E-MpMs), biphasic, and sarcomatoid MpMs (S-MpMs), are characterised by an increased aggressiveness and enhanced levels of EZH2 expression. To investigate the MpM immune contexture along the spectrum of MpM histotypes, an extended in situ analysis was performed on a series of 14 cases. Tumour-infiltrating immune cells and their functionality were assessed by immunohistochemistry, immunofluorescence, qRT-PCR, and flow cytometry analysis. MpMs are featured by a complex immune landscape modulated along the spectrum of MpM variants. Tumour-infiltrating T cells and evidence for pre-existing antitumour immunity are mainly confined to E-MpMs. However, Th1-related immunological features are progressively impaired in the more aggressive forms of E-MpMs and completely lost in S-MpM. Concomitantly, E-MpMs show also signs of active immune suppression, such as the occurrence of Tregs and Bregs and the expression of the immune checkpoint inhibitory molecules PD1 and PDL1. This study enriches the rising rationale for immunotherapy in MpM and points to the E-MpMs as the most immune-sensitive MpM histotypes, but it also suggests that synergistic interventions aimed at modifying the tumour microenvironment (TME) should be considered to make immunotherapy beneficial for these patients.

In plain English

This laboratory study examined surgical tissue from 14 previously untreated patients with malignant peritoneal mesothelioma (cancer of the abdominal lining) in Milan, Italy. They comprised nine epithelioid, two progressed epithelioid, one high-grade epithelioid and two sarcomatoid tumours. The study did not assess asbestos exposure. Using tissue staining, gene tests and (for one patient) flow cytometry, the authors described tumour immune cells. T cells were clearly detectable in eight of nine epithelioid and both progressed tumours. Th1 markers (Tbet and granzyme B) appeared in almost all epithelioid tumours; Tbet was absent from the more aggressive types. The authors judged these T cells likely functionally impaired, as IL2 and TNFA genes were not expressed. Epithelioid tumours also showed immune suppression: regulatory T cells were clearly detectable in four of nine, and suppressive genes were expressed in all nine. No tumour cells expressed PD1 or PDL1. The authors concluded that only epithelioid tumours showed evidence of pre-existing anti-tumour immunity. They also concluded that treatments changing the tumour environment should be considered. They said findings need confirmation, especially for the rarer aggressive 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: Laboratory pathology study of surgical tumour samples, using immunohistochemistry, immunofluorescence, gene-expression testing (qRT-PCR) and flow cytometry
• Who was studied: Formalin-fixed surgical samples from 14 previously untreated patients with malignant peritoneal mesothelioma at the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. There were nine epithelioid, two progressed epithelioid, one high-grade epithelioid and two sarcomatoid cases. Dates of collection were not given.
• Exposure: Not studied. The study examined immune features of tumour tissue. Asbestos is mentioned only in the introduction as part of the disease's causes, and no patient exposure data are reported.
• Main results:
  • CD4+ and CD8+ T cells were clearly detectable in eight of the nine epithelioid tumours and in both progressed epithelioid tumours. None or relatively few CD3+ T cells were present in the high-grade epithelioid tumour and in one of the two sarcomatoid tumours.
  • Almost all epithelioid tumours were positive for the Th1 markers Tbet and granzyme B; only case no. 5 was negative for both.
  • The progressed epithelioid, high-grade epithelioid and sarcomatoid tumours (nos. 10 to 14) showed no Tbet staining. They were also negative for granzyme B, except progressed tumour no. 11, which was strongly positive. The authors suggested this granzyme B staining might come from NK cells.
  • PD1-positive lymphocytes inside the tumour were reported in four of the epithelioid tumours.
  • None of the T-cell-infiltrated samples expressed the IL2 or TNFA genes. The authors took this to mean the infiltrating Th1 cells were not fully activated and likely functionally impaired.
  • The immune-suppressing genes IL6, IL10 and TGFB1 were expressed in all epithelioid cases.
  • Foxp3+ regulatory T cells were clearly detectable in four of the nine epithelioid tumours (nos. 1, 4, 6 and 8) and in the two progressed epithelioid tumours. Table 1 also records occasional Foxp3 staining in other epithelioid cases.
  • In one patient (no. 11), B cells made up 25.29% of tumour-infiltrating immune cells. Of these B cells, 4.19% had a phenotype compatible with regulatory B cells.
  • Organised lymphoid structures were found in 9 of the 11 epithelioid and progressed epithelioid tumours. They were absent from the high-grade epithelioid and sarcomatoid tumours.
  • No tumour cells expressed PD1 or PDL1. Immune cells in five of the nine epithelioid tumours and in one progressed epithelioid tumour (no. 10) were positive for both markers.
• The authors' conclusion: The authors concluded that only epithelioid tumours showed evidence of pre-existing T cell tumour immunity. They judged that a highly suppressive environment limits the likely benefit of immunotherapy. They also concluded that interventions to modify the tumour environment should be considered.
• Limitations the authors state:
  • The authors stated that, with only 14 cases and few of the rarer aggressive types, their data should be confirmed in future studies, especially for the most aggressive variants.

Topics

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

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, Inflammation, Prognosis, Epithelioid, Biphasic Mesothelioma, Sarcomatoid, Immunohistochemistry, Immunotherapy.

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