Immune microenvironment modulation by p14/ARF in Malignant Pleural Mesothelioma

Date 28 September 2019
Event ESMO 2019 Congress
Session Poster Display session 1
Topics Mesothelioma
Presenter Giulia Pasello
Citation Annals of Oncology (2019) 30 (suppl_5): v747-v755. 10.1093/annonc/mdz266
Authors G. Pasello1, L. Urso2, A. Boscolo2, F. Pezzuto3, M. Silic-Benussi4, S. Vuljian5, S. Frega1, L. Bonanno1, M. Schiavon3, F. Rea6, V. Ciminale4, P.F. Conte7, F. Calabrese3
  • 1Oncology 2, Istituto Oncologico Veneto IRCCS, 35128 - Padova/IT
  • 2Department Of Surgery, Oncology And Gastroenterology, University of Padova, 35128 - Padova/IT
  • 3Pathology Unit, Department Of Cardiac,thoracic, Vascular Sciences And Public Health, University of Padova, 35128 - Padova/IT
  • 4Immunology And Molecular Oncology Unit, Istituto Oncologico Veneto IRCCS, 35128 - Padova/IT
  • 5Pathology Unit, Department Of Cardio-thoracic And Vascular Sciences, University of Padova, 35128 - Padova/IT
  • 6Thoracic Surgery Unit, Department Of Cardiac,thoracic, Vascular Sciences And Public Health, University of Padova, 35128 - Padova/IT
  • 7Surgery Oncology And Gastroenterology, Università degli Studi di Padova, 35128 - Padova/IT

Abstract

Background

Tumor Associated Macrophages (TAMs) and ARF-MDM2 pathway seem to be interconnected actors in malignant pleural mesothelioma (MPM) pathogenesis, treatment outcome and prognosis. On the basis of such evidence, this prospective study aims at comparing tumor immune microenvironment (TME) and checkpoint expression (PD-L1) in naïve tumor samples and immune cells in blood samples of ARF+ vs. ARF- MPM.

Methods

Tumor samples were collected at the baseline (T0) in all enrolled patients and at the time of surgery (T1) in resectable patients. Immunohistochemistry was carried out to evaluate p14/ARF, PD-L1, CD3+, CD4+, CD8+ T lymphocytes; CD20+ B-lymphocytes; CD68+ macrophages. Blood samples were collected in a subset of patients at T0 and T1 and analyzed for CD3+CD4+, CD3+CD8+, CD4+CD25+FoxP3+ peripheral T lymphocytes, CD68 + (total) and CD163 + (M2-like) peripheral monocytes by flow cytometry analysis.

Results

Preliminary data on the first 52 chemonaive MPM samples (32 epithelioid, 16 biphasic and 4 sarcomatoid) were evaluated. P14/ARF was detected in 11 patients (21%). P14/ARF+ cases were characterized by higher CD4+ T-lymphocyte percentage (median value 10% vs 1%, p = 0.05), mainly in peritumoral areas, while p14/ARF – cases were characterized by higher CD163+ M2 macrophages percentage (50% vs 40% in p14/ARF+ cases) and higher CD163+/CD68+ ratio (1.3 vs. 1 in p14/ARF+ cases), even though without statistical significance. Paired (T0 and T1) blood samples of five patients were also assessed for CD8+ and CD4+CD25+FoxP3+ T-reg lymphocytes levels change before and after chemotherapy. We observed a T-reg decrease in 2 patients achieving a disease control to first-line platinum-based chemotherapy, while an increase in 3 progressing patients, without major difference between p14/ARF + and p14/ARF- cases.

Conclusions

p14ARF+ MPM samples seem to be characterized by lower CD163+ M2-polarized macrophages and higher CD4+ T lymphocytes. The amount of T-reg in blood samples may be useful to anticipate radiological and/or clinical progression to chemotherapy. Larger case series and wider TME characterization in tissue and immune cells quantification in blood samples are needed to validate our preliminary findings and will be presented at the conference.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Istituto Oncologico Veneto IRCCS.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.