bims-mesote Biomed News
on Mesothelioma
Issue of 2021–07–04
fiveteen papers selected by
Laura Mannarino, Humanitas Research
  1. Ancillary Diagnostic Investigations in Malignant Pleural Mesothelioma.
  2. Molecular Fingerprints of Malignant Pleural Mesothelioma: Not Just a Matter of Genetic Alterations.
  3. Immune Microenvironment and Genetics in Malignant Pleural Mesothelioma.
  4. Immunotherapeutic Approaches in Malignant Pleural Mesothelioma.
  5. The Immune Microenvironment of Malignant Pleural Mesothelioma: A Literature Review.
  6. Inhibition of Human Malignant Pleural Mesothelioma Growth by Mesenchymal Stromal Cells.
  7. Immune checkpoint inhibitors a new player in the therapeutic game of mesothelioma: New reality with new challenges.
  8. Multi-institutional survey of malignant pleural mesothelioma patients in the Hokushin region.
  9. Immunohistochemical Expression of Serine and Arginine-Rich Splicing Factor 1 (SRSF1) in Fluoro-Edenite-Induced Malignant Mesothelioma: A Preliminary Study.
  10. Integrating data from multidisciplinary Management of Malignant Pleural Mesothelioma: a cohort study.
  11. Cellular cannibalism and consequent thrombocytopenia in a patient with bone marrow metastasis of malignant pleural mesothelioma: A case report.
  12. Future Incidence of Malignant Mesothelioma in South Korea: Updated Projection to 2038.
  13. An EBC/Plasma miRNA Signature Discriminates Lung Adenocarcinomas From Pleural Mesothelioma and Healthy Controls.
  14. Mesothelioma.
  15. Activation of DNA Damage Tolerance Pathways May Improve Immunotherapy of Mesothelioma.
  1. Cancers (Basel). 2021 Jun 30. pii: 3291. [Epub ahead of print]13(13):
    Ancillary Diagnostic Investigations in Malignant Pleural Mesothelioma.
    Alex Dipper, Nick Maskell, Anna Bibby.
      For a number of patients presenting with an undiagnosed pleural effusion, frailty, medical co-morbidity or personal choice may preclude the use of pleural biopsy, the gold standard investigation for diagnosis of malignant pleural mesothelioma (MPM). In this review article, we outline the most recent evidence on ancillary diagnostic tests which may be used to support a diagnosis of MPM where histological samples cannot be obtained or where results are non-diagnostic. Immunocytochemical markers, molecular techniques, diagnostic biomarkers and imaging techniques are discussed. No adjunctive test has a sensitivity and specificity profile to support use in isolation; however, correlation of pleural fluid cytology with relevant radiology and supplementary biomarkers can enable an MDT-consensus clinico-radiological-cytological diagnosis to be made where further invasive tests are not possible or not appropriate. Diagnostic challenges surrounding non-epithelioid MPM are recognised, and there is a critical need for reliable and non-invasive investigative tools in this population.
    Keywords:  biomarkers; malignant pleural mesothelioma; pleural effusion
    DOI:  https://doi.org/10.3390/cancers13133291
  2. J Clin Med. 2021 Jun 02. pii: 2470. [Epub ahead of print]10(11):
    Molecular Fingerprints of Malignant Pleural Mesothelioma: Not Just a Matter of Genetic Alterations.
    Eugenia Lorenzini, Alessia Ciarrocchi, Federica Torricelli.
      Malignant pleural mesothelioma (MPM) is a clinical emergency of our time. Being strongly associated with asbestos exposure, incidence of this cancer is ramping up these days in many industrialized countries and it will soon start to increase in many developing areas where the use of this silicate derivate is still largely in use. Deficiency of reliable markers for the early identification of these tumors and the limited efficacy of the currently available therapeutic options are the basis of the impressive mortality rate of MPM. These shortcomings reflect the very poor information available about the molecular basis of this disease. Results of the recently released deep profiling studies point to the epigenome as a central element in MPM development and progression. First, MPM is characterized by a low mutational burden and a highly peculiar set of mutations that hits almost exclusively epigenetic keepers or proteins controlling chromatin organization and function. Furthermore, asbestos does not seem to be associated with a distinctive mutational signature, while the precise mapping of epigenetic changes caused by this carcinogen has been defined, suggesting that alterations in epigenetic features are the driving force in the development of this disease. Last but not least, consistent evidence also indicates that, in the setting of MPM, chromatin rewiring and epigenetic alterations of cancer cells heavily condition the microenvironment, including the immune response. In this review we aim to point to the relevance of the epigenome in MPM and to highlight the dependency of this tumor on chromatin organization and function. We also intend to discuss the opportunity of targeting these mechanisms as potential therapeutic options for MPM.
    Keywords:  epigenome; malignant pleural mesothelioma; target therapies
    DOI:  https://doi.org/10.3390/jcm10112470
  3. Front Oncol. 2021 ;11 684025
    Immune Microenvironment and Genetics in Malignant Pleural Mesothelioma.
    Benjamin Wadowski, Raphael Bueno, Assunta De Rienzo.
      Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with limited therapeutic options beyond surgery and cytotoxic chemotherapy. The success of immune checkpoint inhibition has been found to correlate with expression of immune-related genes such as CD274 (PD-L1) in lung and other solid cancers. However, only a small subset of MPM patients respond to checkpoint inhibition, and this response has been varied and unpredictable across several clinical trials. Recent advances in next-generation sequencing (NGS) technology have improved our understanding of the molecular features of MPM, also with respect to its genetic signature and how this impacts the immune microenvironment. This article will review current evidence surrounding the interplay between MPM genetics, including epigenetics and transcriptomics, and the immune response.
    Keywords:  checkpoint; genomics; immune; mesothelioma; microenvironment; transcriptomics
    DOI:  https://doi.org/10.3389/fonc.2021.684025
  4. Cancers (Basel). 2021 Jun 04. pii: 2793. [Epub ahead of print]13(11):
    Immunotherapeutic Approaches in Malignant Pleural Mesothelioma.
    Rita Terenziani, Silvia Zoppi, Claudia Fumarola, Roberta Alfieri, Mara Bonelli.
      Malignant pleural mesothelioma (MPM) is a rare and aggressive malignant disease affecting the mesothelium, commonly associated to asbestos exposure. The current therapeutic actions, based on cisplatin/pemetrexed treatment, are limited due to the late stage at which most patients are diagnosed and to the intrinsic chemo-resistance of the tumor. Another relevant point is the absence of approved therapies in the second line setting following progression of MPM after chemotherapy. Considering the poor prognosis of the disease and the fact that the incidence of this tumor is expected to increase in the next decade, novel therapeutic approaches are urgently needed. In the last few years, several studies have investigated the efficacy and safety of immune-checkpoint inhibitors (ICIs) in the treatment of unresectable advanced MPM, and a number of trials with immunotherapeutic agents are ongoing in both first line and second line settings. In this review, we describe the most promising emerging immunotherapy treatments for MPM (ICIs, engineered T cells to express chimeric antigen receptors (CARs), dendritic cells (DCs) vaccines), focusing on the biological and immunological features of this tumor as well as on the issues surrounding clinical trial design.
    Keywords:  CTLA-4; PD-1/PD-L1; VISTA; immune checkpoint inhibitors; immunotherapy; malignant pleural mesothelioma
    DOI:  https://doi.org/10.3390/cancers13112793
  5. Cancers (Basel). 2021 Jun 26. pii: 3205. [Epub ahead of print]13(13):
    The Immune Microenvironment of Malignant Pleural Mesothelioma: A Literature Review.
    Anne-Laure Désage, Georgia Karpathiou, Michel Peoc'h, Marios E Froudarakis.
      Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour with a poor prognosis, associated with asbestos exposure. Nowadays, treatment is based on chemotherapy with a median overall survival of less than two years. This review highlights the main characteristics of the immune microenvironment in MPM with special emphasis on recent biological advances. The MPM microenvironment is highly infiltrated by tumour-associated macrophages, mainly M2-macrophages. In line with infiltration by M2-macrophages, which contribute to immune suppression, other effectors of innate immune response are deficient in MPM, such as dendritic cells or natural killer cells. On the other hand, tumour infiltrating lymphocytes (TILs) are also found in MPM, but CD4+ and CD8+ TILs might have decreased cytotoxic effects through T-regulators and high expression of immune checkpoints. Taken together, the immune microenvironment is particularly heterogeneous and can be considered as mainly immunotolerant or immunosuppressive. Therefore, identifying molecular vulnerabilities is particularly relevant to the improvement of patient outcomes and the assessment of promising treatment approaches.
    Keywords:  exhausted T-cells; immune checkpoints; immune microenvironment; malignant pleural mesothelioma; tumour infiltrating lymphocytes; tumour-associated macrophages
    DOI:  https://doi.org/10.3390/cancers13133205
  6. Cells. 2021 Jun 08. pii: 1427. [Epub ahead of print]10(6):
    Inhibition of Human Malignant Pleural Mesothelioma Growth by Mesenchymal Stromal Cells.
    Valentina Coccè, Silvia La Monica, Mara Bonelli, Giulio Alessandri, Roberta Alfieri, Costanza Annamaria Lagrasta, Denise Madeddu, Caterina Frati, Lisa Flammini, Daniela Lisini, Angela Marcianti, Eugenio Parati, Francesca Paino, Aldo Giannì, Giampietro Farronato, Angela Falco, Lorenzo Spaggiari, Francesco Petrella, Augusto Pessina.
       BACKGROUND: Malignant Pleural Mesothelioma (MPM) is an aggressive tumor that has a significant incidence related to asbestos exposure with no effective therapy and poor prognosis. The role of mesenchymal stromal cells (MSCs) in cancer is controversial due to their opposite effects on tumor growth and in particular, only a few data are reported on MSCs and MPM.
    METHODS: We investigated the in vitro efficacy of adipose tissue-derived MSCs, their lysates and secretome against different MPM cell lines. After large-scale production of MSCs in a bioreactor, their efficacy was also evaluated on a human MPM xenograft in mice.
    RESULTS: MSCs, their lysate and secretome inhibited MPM cell proliferation in vitro with S or G0/G1 arrest of the cell cycle, respectively. MSC lysate induced cell death by apoptosis. The efficacy of MSC was confirmed in vivo by a significant inhibition of tumor growth, similar to that produced by systemic administration of paclitaxel. Interestingly, no tumor progression was observed after the last MSC treatment, while tumors started to grow again after stopping chemotherapeutic treatment.
    CONCLUSIONS: These data demonstrated for the first time that MSCs, both through paracrine and cell-to-cell interaction mechanisms, induced a significant inhibition of human mesothelioma growth. Since the prognosis for MPM patients is poor and the options of care are limited to chemotherapy, MSCs could provide a potential new therapeutic approach for this malignancy.
    Keywords:  cell therapy; malignant pleural mesothelioma (MPM); mesenchymal stromal cells; mesothelioma
    DOI:  https://doi.org/10.3390/cells10061427
  7. Cancer Treat Rev. 2021 Jun 16. pii: S0305-7372(21)00098-0. [Epub ahead of print]99 102250
    Immune checkpoint inhibitors a new player in the therapeutic game of mesothelioma: New reality with new challenges.
    Kaushal Parikh, Lizza E L Hendriks, Paolo Bironzo, Jordi Remon.
      Malignant pleural mesothelioma (MPM) is a rare and orphan thoracic malignancy, with a poor prognosis as the majority of patients are diagnosed with unresectable MPM, with no significant improvements in the therapeutic strategy for over a decade. However, the recent approval of immune checkpoint inhibitors (ICI) in treatment-naïve patients with unresectable MPM marks a significant step forward and hope for the treatment of this disease. In this narrative review, we discuss the biological rationale to use ICI in the treatment of MPM. We summarize the current evidence for the efficacy of ICI in MPM and discuss several unresolved challenges regarding the use of ICI in this disease, such as the best upfront immune approach in MPM (ICI versus ICI plus chemotherapy), the optimal sequential treatment strategy according to the first-line treatment, and the potential role of predictive biomarkers.
    Keywords:  Immune checkpoint inhibitors; Ipilimumab; Mesothelioma; Nivolumab; Pembrolizumab
    DOI:  https://doi.org/10.1016/j.ctrv.2021.102250
  8. J Cancer Res Clin Oncol. 2021 Jun 29.
    Multi-institutional survey of malignant pleural mesothelioma patients in the Hokushin region.
    Hidetaka Uramoto, Tomoya Takiguchi, Tomonobu Koizumi, Azusa Tanimoto, Ryuji Hayashi, Yozo Nakazawa, Ken-Ichi Ito, Mitsutoshi Nakada, Yasuo Hirono, Yoshikazu Nishino, Seiji Yano.
       BACKGROUND: Malignant pleural mesothelioma (MPM) is a major occupational and environmental neoplasm. The purpose of this study was to validate the clinical and epidemiological factors, diagnosis, and initial treatment among MPM patients in the Hokushin region.
    METHODS: We surveyed retrospective data from 152,921 cancer patients in 22 principal hospitals.
    RESULTS: A total of 166 MPM cases were newly diagnosed. These patients consisted of 136 men and 30 women, with a median age of 69 years. We estimated the incidence rate for MPM to be 0.55 cases per 100,000 person-years in this study. The ratio per 100,000 population-years was 0.39 in Fukui, 0.60 in Ishikawa, 1.02 in Toyama and 0.35 in Nagano. Forty-five patients were discovered when diagnosed incidentally in patients under observations for other diseases. Forty-six cases were diagnosed as localized disease, while 13 had accompanying regional lymph node metastasis. Furthermore, 44 cases showed infiltration into adjacent organs. A histo-cytological diagnosis was made in 164 cases (98.8%). A surgical approach, chemotherapy, and radiotherapy were performed for 33, 88, and 6 patients, respectively, while 44 patients (26.5%) received best supportive care. Multimodality therapy was conducted in just 3.0% of the MPM patients CONCLUSION: MPM has a tragically rapid progression if discovered under observations for other diseases. Workers in health-related fields should be on high alert for aggressive MPM. Better evaluation and multi-disciplinary approaches to MPM in these regions are needed to optimize multimodality therapy.
    Keywords:  Cancer registration; Cancer screening; Ganpro database; Hokushin region; Malignant pleural mesothelioma
    DOI:  https://doi.org/10.1007/s00432-021-03699-z
  9. Int J Environ Res Public Health. 2021 Jun 09. pii: 6249. [Epub ahead of print]18(12):
    Immunohistochemical Expression of Serine and Arginine-Rich Splicing Factor 1 (SRSF1) in Fluoro-Edenite-Induced Malignant Mesothelioma: A Preliminary Study.
    Giuseppe Broggi, Giuseppe Angelico, Veronica Filetti, Caterina Ledda, Claudia Lombardo, Ermanno Vitale, Venerando Rapisarda, Carla Loreto, Rosario Caltabiano.
      The Serine and Arginine-Rich Splicing Factor 1 (SRSF1) has a proto-oncogenic function, being associated with angiogenesis and frequently overexpressed in many human malignant neoplasms. Its immunohistochemical expression has never been investigated in malignant pleural mesothelioma (MPM). We evaluated SRSF1 immunoexpression and its possible relation to angiogenesis in a selected cohort of 10 fluoro-edenite(FE)-induced MPM cases.
    METHODS: Immunohistochemical analyses with an anti-SRSF1 antibody were performed. We interpreted the cases as positive if tumor cell nuclei were stained; a semi-quantitative analysis of the cases was performed by evaluating the intensity of staining and the percentage of tumor positive cells. A microvessel density (MVD) count was also performed.
    RESULTS: High and low immunoexpressions of SRSF1 were seen in six and four MPMs, respectively. A trend of shorter overall survival was found in FE-induced MPM patients with SRSF1 overexpression. In addition, a significant association between high-MVD and high SRSF1 immunoexpression (p = 0.0476) was found.
    CONCLUSIONS: SRSF1 appears to be involved in MPM pathogenesis and its immunoexpression may represent a prognostic biomarker capable of identifying subgroups of patients with different prognosis. However, given the preliminary nature of the present study, further investigations on larger series, and additional in vitro studies, are required to validate our findings.
    Keywords:  SRSF1; fluoro-edenite; malignant mesothelioma; prognostic factor
    DOI:  https://doi.org/10.3390/ijerph18126249
  10. BMC Cancer. 2021 Jul 01. 21(1): 762
    Integrating data from multidisciplinary Management of Malignant Pleural Mesothelioma: a cohort study.
    Laura Saracino, Chandra Bortolotto, Stefano Tomaselli, Elia Fraolini, Matteo Bosio, Giulia Accordino, Francesco Agustoni, David M Abbott, Emma Pozzi, Dimitrios Eleftheriou, Patrizia Morbini, Pietro Rinaldi, Cristiano Primiceri, Andrea Lancia, Patrizia Comoli, Andrea R Filippi, Giulia M Stella.
       BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy that most commonly affects the pleural layers. MPM has a strong association with asbestos, mainly caused by exposure to its biopersistent fibers in at least 80% of cases. Individuals with a chronic exposure to asbestos might develop disease with a 20-40-year latency with few or no symptoms. Such has been the case in the Italian regions of Piedmont and Lombardy, where industrial production of materials laden with asbestos, mainly cements, has been responsible for the onset of a large epidemic. Since 2018, a multidisciplinary team at San Matteo hospital in Pavia has been collecting data on over 100 patients with MPM. The main goal of this project is to define and describe an integrated profile for each MPM case at diagnosis by using data mining and partition analysis.
    METHODS: Here we bring together exhaustive epidemiologic, histologic and radiologic data of 88 MPM patients that came to our observation and draw correlations with predictive and prognostic significance.
    RESULTS: The median overall survival (OS) was 15.6 months. Most patients presented with pleural effusion, irrespective of disease stage. Quite unexpectedly, no statistically significant association was demonstrated between OS and TNM disease stage at diagnosis. Although average OS is similar in male and female patients, partition analysis of data underlined a significant differential hierarchy of predictor categories based on patient gender. In females with no smoking history, full chemotherapeutic regimens are associated with better outcomes. Moreover, concerning second line treatments, vinorelbine emerged as the most advantageous choice for female patients, whereas in the male subgroup no statistically significant difference resulted between gemcitabine and vinorelbine.
    CONCLUSION: A multidisciplinary approach to MPM is mandatory to define better therapeutic approaches, personalize the management and improve patient outcomes.
    Keywords:  Asbestos; Imaging; Mesothelioma; Multidisciplinary team
    DOI:  https://doi.org/10.1186/s12885-021-08532-x
  11. Mol Clin Oncol. 2021 Aug;15(2): 163
    Cellular cannibalism and consequent thrombocytopenia in a patient with bone marrow metastasis of malignant pleural mesothelioma: A case report.
    Megumi Nishikubo, Yasuo Kin, Shinya Tane, Koji Nakamura, Yoshimi Miyagi, Akiko Miura, Wataru Nishio, Hideto Senzaki, Kazuya Uchino.
      Cellular cannibalism is a tumor activity where a cell is engulfed by another cell. This process promotes tumor cell survival under unfavorable conditions. The current report describes an extremely rare case of thrombocytopenia resulting from cellular cannibalism in a patient with bone marrow metastasis due to malignant pleural mesothelioma (MPM). A 77-year-old male presented with hemothorax and thrombocytopenia. He was diagnosed with MPM of the sarcomatoid cell type. However, his disease progressed rapidly and he died 11 days after admission. Bone marrow aspiration revealed metastatic MPM cells that had engulfed other blood cells. Accordingly, the observed thrombocytopenia was attributed to cellular cannibalism by metastatic MPM tumor cells. To the best of our knowledge, this is the first reported case of thrombocytopenia due to cellular cannibalism in a patient with this type of malignancy (MPM). The results suggested that although MPM rarely metastasizes to the bone marrow, bone marrow aspiration could be useful in such cases.
    Keywords:  apoptosis; blood cells; bone marrow; cell survival; cellular cannibalism; disseminated intravascular coagulation; drug resistance; mesothelioma; metastasis; thrombocytopenia
    DOI:  https://doi.org/10.3892/mco.2021.2325
  12. Int J Environ Res Public Health. 2021 Jun 19. pii: 6614. [Epub ahead of print]18(12):
    Future Incidence of Malignant Mesothelioma in South Korea: Updated Projection to 2038.
    Kyeongmin Kwak, Sung-Il Cho, Domyung Paek.
      Malignant mesothelioma (MM) is a cancer that is largely caused by exposure to asbestos. Although asbestos is no longer used in South Korea, the incidence of MM continues to increase due to its long latent period. We aimed to update the previous prediction of MM incidence until 2038. We predicted the incidence of MM over the next 20 years (2019-2038) in South Korea using Møller's age-period-cohort (APC) model and a Poisson regression model based on asbestos consumption. The APC model predicted that the crude incidence rate would increase sharply in men and slowly in women. Despite the sex discrepancy in the rate of increase, the incidence rate for both sexes is expected to continue increasing until 2038. In the Poisson model, the crude incidence rate was predicted to increase continuously until 2038, and far more cases of MM were predicted to occur compared with the results of the APC model. When compared with actual incidence data, the APC model was deemed more suitable than the Poisson model. The APC model predicted a continuous increase over the next 20 years with no peak, suggesting that the incidence of MM will continue to rise far into the future.
    Keywords:  NORDPRED; Poisson regression; age-period-cohort model; asbestos; malignant mesothelioma; mesothelioma; prediction model
    DOI:  https://doi.org/10.3390/ijerph18126614
  13. Front Oncol. 2021 ;11 643280
    An EBC/Plasma miRNA Signature Discriminates Lung Adenocarcinomas From Pleural Mesothelioma and Healthy Controls.
    Alice Faversani, Chiara Favero, Laura Dioni, Angela Cecilia Pesatori, Valentina Bollati, Matteo Montoli, Valeria Musso, Andrea Terrasi, Nicola Fusco, Mario Nosotti, Valentina Vaira, Alessandro Palleschi.
       Background: Despite significant improvement in screening programs for cancers of the respiratory district, especially in at-risk subjects, early disease detection is still a major issue. In this scenario, new molecular and non-invasive biomarkers are needed to improve early disease diagnosis.
    Methods: We profiled the miRNome in exhaled breath condensate (EBC) and plasma samples from fourteen patients affected by lung AdCa, nine healthy subjects. miRNA signatures were then analyzed in another neoplasia of the respiratory district, i.e. pleural mesothelioma (n = 23) and subjects previously exposed to asbestos were used as controls for this cohort (n = 19). Selected miRNAs were analyzed in purified pulmonary neoplastic or normal epithelial and stromal cell subpopulation from AdCa patients. Finally, the plasmatic miRNA signature was analyzed in a publicly available cohort of NSCLC patients for data validation and in silico analysis was performed with predicted miRNA targets using the multiMiR tool and STRING database.
    Results: miR-597-5p and miR-1260a are significantly over-expressed in EBC from lung AdCa and are associated with AdCa. Similarly, miR-1260a is also up-regulated in the plasma of AdCa patients together with miR-518f-3p and correlates with presence of lung cancer, whereas let-7f-5p is under-expressed. Analysis of these circulating miRNAs in pleural mesothelioma cases confirmed that up-regulation of miR-518f-3p, -597-5p and -1260a, is specific for lung AdCa. Lastly, quantification of the miRNAs in laser-assisted microdissected lung tissues revealed that miR-518f-3p, 597-5p and miR-1260a are predominantly expressed in tumor epithelial cells. Validation analysis confirmed miR-518f-3p as a possible circulating biomarker of NSCLC. In silico analysis of the potentially modulated biological processes by these three miRNAs, shows that tumor bioenergetics are the most affected pathways.
    Conclusions: Overall, our data suggest a 3-miRNAs signature as a non-invasive and accurate biomarker of lung AdCa. This approach could supplement the current screening approaches for early lung cancer diagnosis.
    Keywords:  exhaled breath condensate; liquid biopsy; lung cancer; malignant pleural mesothelioma; microRNA; volatile biopsy
    DOI:  https://doi.org/10.3389/fonc.2021.643280
  14. Cancers (Basel). 2021 Jun 23. pii: 3127. [Epub ahead of print]13(13):
    Mesothelioma.
    Marcello Deraco.
      Malignant mesothelioma is a disease affecting serosal surfaces derived from the mesothelium comprising the pleura, peritoneum, pericardium, and tunica vaginalis testis [...].
    DOI:  https://doi.org/10.3390/cancers13133127
  15. Cancers (Basel). 2021 Jun 27. pii: 3211. [Epub ahead of print]13(13):
    Activation of DNA Damage Tolerance Pathways May Improve Immunotherapy of Mesothelioma.
    Hélène Brossel, Alexis Fontaine, Clotilde Hoyos, Majeed Jamakhani, Mégane Willems, Malik Hamaidia, Luc Willems.
      Immunotherapy based on two checkpoint inhibitors (ICI), programmed cell death 1 (PD-1, Nivolumab) and cytotoxic T-lymphocyte 4 (CTLA-4, Ipilimumab), has provided a significant improvement in overall survival for malignant mesothelioma (MM). Despite this major breakthrough, the median overall survival of patients treated with the two ICIs only reached 18.1 months vs. 14 months in standard chemotherapy. With an objective response rate of 40%, only a subset of patients benefits from immunotherapy. A critical step in the success of immunotherapy is the presentation of tumor-derived peptides by the major histocompatibility complex I (MHC-I) of tumor cells. These neoantigens are potentially immunogenic and trigger immune responses orchestrated by cytotoxic cells. In MM, tumor development is nevertheless characterized by a low mutation rate despite major structural chromosomal rearrangements driving oncogenesis (BAP1, NF2, CDKN2AB). In this opinion, we propose to investigate an approach based on the mechanisms of the DNA damage tolerance (DDT) pathways to increase the frequency of non-synonymous mutations. The idea is to transiently activate the error-prone DDT in order to generate neoantigens while preserving a fully competent antitumor immune response.
    Keywords:  DNA damage response; chemoresistance; immune checkpoint inhibitor; immunotherapy; mesothelioma; tolerance to DNA damage
    DOI:  https://doi.org/10.3390/cancers13133211
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