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PDL1 has cell autonomous functions in mesothelioma and its targeting might be effective beyond its role in the antitumoral immune response
4th World Congress on SURGICAL PATHOLOGY AND ONCOLOGY RESEARCH
October 17, 2022 | Webinar
Francesca Pentimalli, Caterina Costa, Daniela Barone, Giuseppe Portella, Luciano Mutti and Antonio Giordano
LUM University, Italy
National Cancer Institute, Italy
National Cancer Institute, Italy
University of Naples, Italy
University of Salford, United Kingdom
Temple University, Pennsylvania
Scientific Tracks Abstracts : J Clin Path Lab Med
Abstract:
Malignant pleural mesothelioma is an aggressive cancer caused by asbestos exposure. All three main histotypes of mesothelioma, including the epithelioid, sarcomatoid and biphasic, have a poor prognosis ??? often less than two years from diagnosis ??? despite multimodal therapy, consisting of chemotherapy, surgery (when possible) and radiotherapy. Recently, immunotherapy has been proposed for the first line treatment of pleural mesothelioma. However, in a comparative effectiveness study of the three main randomized clinical trials since 2003, defining first line treatment of pleural mesothelioma, we showed that selection criteria, fragility and censoring patterns of the trials may affect the original conclusions and the proposed nivolumab plus ipilimumab combination does not seem to provide significant improvements (1). Various precision immunotherapy approaches are directed against the immune checkpoint protein PDL1. We previously showed that in mesothelioma PDL1 is highly expressed, probably as a consequence of a deregulated p53 pathway, which fails to trigger the expression of various microRNAs targeting PDL1 such as mir320a and mir34 (2). We then investigated whether PDL1 could also exert cell autonomous functions beyond its role in the immune checkpoint. Indeed, we found that silencing PDL1 in mesothelioma cell lines reduces cell growth, colony formation, migration rate and the ability to form spheres. Stem cell markers are also consistently reduced upon shRNA-mediated PDL1 silencing. Also, we found that PDL1 is anticorrelated with mir145, another p53 regulated microRNA. Overall, our data reinforce the idea that reactivating p53 potential could be a feasible strategy against mesothelioma (3) and suggest that targeting PDL1 could decrease mesothelioma malignant features independently of the immune response.
References :
1. Meirson T, Pentimalli F, Cerza F, Baglio G, Gray SG, Correale P, Krstic-Demonacos M, Markel G, Giordano A, Bomze D, Mutti L. Comparison of 3 Randomized Clinical Trials of Frontline Therapies for Malignant Pleural Mesothelioma. JAMA Netw Open. 2022 Mar 1;5(3):e221490.
2. Costa C, Indovina P, Mattioli E, Forte IM, Iannuzzi CA, Luzzi L, Bellan C, De Summa S, Bucci E, Di Marzo D, De Feo M, Mutti L, Pentimalli F, Giordano A. P53-regulated miR-320a targets PDL1 and is downregulated in malignant mesothelioma. Cell Death Dis. 2020 Sep 14;11(9):748.
3. Di Marzo D, Forte IM, Indovina P, Di Gennaro E, Rizzo V, Giorgi F, Mattioli E, Iannuzzi CA, Budillon A, Giordano A, Pentimalli F. Pharmacological targeting of p53 through RITA is an effective antitumoral strategy for malignant pleural mesothelioma. Cell Cycle. 2014;13(4):652-65.
Biography:
Francesca Pentimalli is associate professor of general pathology at the department of medicine & surgery of LUM University, Casamassima, BA, Italy. She obtained her MSc degree in biological sciences and PhD in molecular and cellular genetics at the university of Naples Federico II, Italy, where she also completed the specialization programme in clinical pathology and clinical biochemistry. She authored/co-authored over a hundred peer-review articles in the field of cancer genetics and therapeutics.
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