bims-mesote Biomed News
on Mesothelioma
Issue of 2023–04–09
nine papers selected by
Laura Mannarino, Humanitas Research
  1. Genetic analysis of familial predisposition in the pathogenesis of malignant pleural mesothelioma.
  2. Excess of blood eosinophils prior to therapy correlates with worse prognosis in mesothelioma.
  3. Survival benefit after radiotherapy for patients with malignant pleural mesothelioma: A propensity score-matched study.
  4. A role for macrophages under cytokine control in mediating resistance to ADI-PEG20 (pegargiminase) in ASS1-deficient mesothelioma.
  5. Three distinct mechanisms underlying human γδ T cell-mediated cytotoxicity against malignant pleural mesothelioma.
  6. A study of somatic BRCA variants and their putative effect on protein properties in malignant mesothelioma.
  7. Association of mesothelioma deaths with the neighborhood asbestos exposure due to a large-scale asbestos-cement plant.
  8. Comprehensive evaluation of surrogate endpoints to predict overall survival in trials with PD1/PD-L1 immune checkpoint inhibitors plus chemotherapy.
  9. BAP1 as a guardian of genome stability: implications in human cancer.
  1. J Cancer Res Clin Oncol. 2023 Apr 07.
    Genetic analysis of familial predisposition in the pathogenesis of malignant pleural mesothelioma.
    Muhittin Akarsu, Güntülü Ak, Emine Dündar, Muzaffer Metintaş.
       PURPOSE: Mesothelioma is the primary tumor of the mesothelial cell membrane. The most important etiology is asbestos exposure. The development of malignant mesothelioma in very few of the population exposed to asbestos and its frequent occurrence in some families may be significant in terms of genetic predisposition. Again, the presence of relatives with mesothelioma who did not have asbestos contact strengthens this argument. This disease, which has limited treatment options and has a poor prognosis, revealing a genetic predisposition, if any, may prolong survival with early diagnosis and effective treatment.
    METHODS: Based on the genetic predisposition idea, we diagnosed and followed a total of ten individuals of relatives with mesothelioma. DNA was isolated from peripheral blood and whole genome sequencing analysis was done. Common gene mutations in ten individuals were filtered using bioinformatics. After this filter, from the remaining variants, very rare in the population and damaging mutations are selected.
    RESULTS: Eight thousand six hundred and twenty-two common variants have been identified in ten individuals with this analysis. In total, 120 variants were found on 37 genes in 15 chromosomes. These genes are PIK3R4, SLC25A5, ITGB6, PLK2, RAD17, HLA-B, HLA-DRB1, HLA-DQB1, GRM, IL20RA, MAP3K7, RIPK2, and MUC16.
    CONCLUSION: Our finding, PIK3R4 gene, is directly associated with mesothelioma development. Twelve genes, which are associated with cancer, were detected in literature. Additional studies, which scan first-degree relatives of individual, are needed to find the specific gene region.
    Keywords:  Familial predisposition; Genetics; Genome sequencing; Mesothelioma
    DOI:  https://doi.org/10.1007/s00432-023-04730-1
  2. Front Immunol. 2023 ;14 1148798
    Excess of blood eosinophils prior to therapy correlates with worse prognosis in mesothelioma.
    Mégane Willems, Arnaud Scherpereel, Eric Wasielewski, Jo Raskin, Hélène Brossel, Alexis Fontaine, Mélanie Grégoire, Louise Halkin, Majeed Jamakhani, Vincent Heinen, Renaud Louis, Bernard Duysinx, Malik Hamaidia, Luc Willems.
       Background: Only a fraction of patients with malignant pleural mesothelioma (MPM) will respond to chemo- or immunotherapy. For the majority, the condition will irremediably relapse after 13 to 18 months. In this study, we hypothesized that patients' outcome could be correlated to their immune cell profile. Focus was given to peripheral blood eosinophils that, paradoxically, can both promote or inhibit tumor growth depending on the cancer type.
    Methods: The characteristics of 242 patients with histologically proven MPM were retrospectively collected in three centers. Characteristics included overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR). The mean absolute eosinophil counts (AEC) were determined by averaging AEC data sets of the last month preceding the administration of chemo- or immunotherapy.
    Results: An optimal cutoff of 220 eosinophils/µL of blood segregated the cohort into two groups with significantly different median OS after chemotherapy (14 and 29 months above and below the threshold, p = 0.0001). The corresponding two-year OS rates were 28% and 55% in the AEC ≥ 220/µL and AEC < 220/µL groups, respectively. Based on shorter median PFS (8 vs 17 months, p < 0.0001) and reduced DCR (55.9% vs 35.2% at 6 months), the response to standard chemotherapy was significantly affected in the AEC ≥ 220/µL subset. Similar conclusions were also drawn from data sets of patients receiving immune checkpoint-based immunotherapy.
    Conclusion: In conclusion, baseline AEC ≥ 220/µL preceding therapy is associated with worse outcome and quicker relapse in MPM.
    Keywords:  chemotherapy; cisplatin; eosinophils; malignant pleural mesothelioma; pemetrexed
    DOI:  https://doi.org/10.3389/fimmu.2023.1148798
  3. MedComm (2020). 2023 Apr;4(2): e241
    Survival benefit after radiotherapy for patients with malignant pleural mesothelioma: A propensity score-matched study.
    Liyou Lian, Huijun Lei, Shuwen Cheng, Rujie Zheng, Hongxia Yao, Jinfei Chen, Tianhui Chen.
      
    DOI:  https://doi.org/10.1002/mco2.241
  4. Pharmacol Rep. 2023 Apr 03.
    A role for macrophages under cytokine control in mediating resistance to ADI-PEG20 (pegargiminase) in ASS1-deficient mesothelioma.
    Melissa M Phillips, Iuliia Pavlyk, Michael Allen, Essam Ghazaly, Rosalind Cutts, Josephine Carpentier, Joe Scott Berry, Callum Nattress, Shenghui Feng, Gunnel Hallden, Claude Chelala, John Bomalaski, Jeremy Steele, Michael Sheaff, Frances Balkwill, Peter W Szlosarek.
       BACKGROUND: Pegylated arginine deiminase (ADI-PEG20; pegargiminase) depletes arginine and improves survival outcomes for patients with argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM). Optimisation of ADI-PEG20-based therapy will require a deeper understanding of resistance mechanisms, including those mediated by the tumor microenvironment. Here, we sought to reverse translate increased tumoral macrophage infiltration in patients with ASS1-deficient MPM relapsing on pegargiminase therapy.
    METHODS: Macrophage-MPM tumor cell line (2591, MSTO, JU77) co-cultures treated with ADI-PEG20 were analyzed by flow cytometry. Microarray experiments of gene expression profiling were performed in ADI-PEG20-treated MPM tumor cells, and macrophage-relevant genetic "hits" were validated by qPCR, ELISA, and LC/MS. Cytokine and argininosuccinate analyses were performed using plasma from pegargiminase-treated patients with MPM.
    RESULTS: We identified that ASS1-expressing macrophages promoted viability of ADI-PEG20-treated ASS1-negative MPM cell lines. Microarray gene expression data revealed a dominant CXCR2-dependent chemotactic signature and co-expression of VEGF-A and IL-1α in ADI-PEG20-treated MPM cell lines. We confirmed that ASS1 in macrophages was IL-1α-inducible and that the argininosuccinate concentration doubled in the cell supernatant sufficient to restore MPM cell viability under co-culture conditions with ADI-PEG20. For further validation, we detected elevated plasma VEGF-A and CXCR2-dependent cytokines, and increased argininosuccinate in patients with MPM progressing on ADI-PEG20. Finally, liposomal clodronate depleted ADI-PEG20-driven macrophage infiltration and suppressed growth significantly in the MSTO xenograft murine model.
    CONCLUSIONS: Collectively, our data indicate that ADI-PEG20-inducible cytokines orchestrate argininosuccinate fuelling of ASS1-deficient mesothelioma by macrophages. This novel stromal-mediated resistance pathway may be leveraged to optimize arginine deprivation therapy for mesothelioma and related arginine-dependent cancers.
    Keywords:  ADI-PEG20; ASS1; Arginine deprivation; Macrophages; Mesothelioma
    DOI:  https://doi.org/10.1007/s43440-023-00480-6
  5. Front Immunol. 2023 ;14 1058838
    Three distinct mechanisms underlying human γδ T cell-mediated cytotoxicity against malignant pleural mesothelioma.
    Yasuhiro Umeyama, Hirokazu Taniguchi, Hiroshi Gyotoku, Hiroaki Senju, Hiromi Tomono, Shinnosuke Takemoto, Hiroyuki Yamaguchi, Mohammed S O Tagod, Masashi Iwasaki, Yoshimasa Tanaka, Hiroshi Mukae.
       Introduction: Malignant pleural mesothelioma (MPM) is a rare and highly aggressive thoracic tumor with poor prognosis and limited therapeutic options. Although immune checkpoint inhibitors exhibit a promising effect in some patients with unresectable MPM in clinical trials, the majority of MPM patients show only modest response rates to the currently available treatments. It is thus imperative to develop novel and innovative therapeutic modalities for MPM, including immune effector cell-based therapies.
    Methods: γδ T cells were expanded using tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino) ethylidene-1,1-bisphosphonate (PTA) and interleukin-2, and the therapeutic potential of γδ T cells was examined through analyzing cell surface markers and cellular cytotoxicity against MPM in vitro using a europium chelate-based time-resolved fluorescence assay system and a luciferase-based luminescence assay system.
    Results and discussion: We successfully expanded γδ T cells from peripheral blood mononuclear cells of healthy donors and MPM patients. γδ T cells expressed natural killer receptors such as NKG2D and DNAM-1 and exhibited a moderate level of cytotoxicity to MPM cells in the absence of antigens. The inclusion of PTA, (E)-4-hydroxy-3- methylbut-2-enyl diphosphate (HMBPP) or zoledronic acid (ZOL) induced a TCR-dependent cytotoxicity in γδ T cells and secreted interferon-γ (IFN-γ). In addition, γδ T cells expressing CD16 exhibited a significant level of cytotoxicity against MPM cells in the presence of an anti-epidermal growth factor receptor (EGFR) mAb, at lower concentrations than in clinical settings, whereas a detectable level of IFN-γ was not produced. Taken together, γδ T cells showed cytotoxic activity against MPM in three distinct mechanisms through NK receptors, TCRs and CD16. Since major histocompatibility complex (MHC) molecules are not involved in the recognition, both autologous and allogeneic γδ T cells could be used for the development of γδ T cell-based adoptive immunotherapy for MPM.
    Keywords:  immunotherapy; malignant pleural mesothelioma; natural killer receptor; nitrogen-containing bisphosphonate prodrug; phosphoantigen; γδ T cell
    DOI:  https://doi.org/10.3389/fimmu.2023.1058838
  6. Pleura Peritoneum. 2023 Mar;8(1): 19-25
    A study of somatic BRCA variants and their putative effect on protein properties in malignant mesothelioma.
    Kritika Krishnamurthy, Kei Shing Oh, Sarah Alghamdi, Vathany Sriganeshan, Robert Poppiti.
       Objectives: The aim of this study is to analyze the prevalence of somatic mutations in BRCA1 and BRCA2 in malignant mesothelioma and their putative impact on protein properties.
    Methods: Eighteen cases of malignant mesothelioma were retrieved from the archives and for next generation sequencing analysis of BRCA1 and BRCA2 genes. Variants were analyzed using Ensembl VEP17, Polyphen 2.0 software, SIFT software, MutpredV2, and SWISS-MODEL homology-modeling pipeline server.
    Results: BRCA2 variants were found in significantly higher percentage (22%) of cases (p=0.02). Five missense variants were identified. These were p.A2351P, p.T2250A, p.A895V, pG1771D, and p.R2034C. The SIFT scores of all except one were ≥ 0.03. The Polyphen scores of these four alterations were ≤0.899. In case of p.A2315, the SIFT score was 0.01, while the Polyphen 2 score was 0.921. MutPred2 scores were ≤0.180 for all. Loss of intrinsic disorder was predicted (Pr=0.32, p=0.07) for p.R2034C, while gain of intrinsic disorder was predicted for p.A2351P (Pr=0.36, p=0.01) and p.G1771D (Pr=0.34, p=0.02).
    Conclusions: BRCA2 somatic variants were identified in 22% cases of malignant mesotheliomas in this study. The variants localize more frequently to the disordered regions of the protein and are predicted to affect the level of disorder.
    Keywords:  BRCA1; BRCA2; brca; disorder of proteins; malignant mesothelioma; somatic variants
    DOI:  https://doi.org/10.1515/pp-2023-0003
  7. Cancer Sci. 2023 Apr 03.
    Association of mesothelioma deaths with the neighborhood asbestos exposure due to a large-scale asbestos-cement plant.
    Yuri Kitamura, Ling Zha, Rong Liu, Masayuki Shima, Tomoki Nakaya, Norio Kurumatani, Shinji Kumagai, Junko Goji, Tomotaka Sobue.
      A causal relationship between mesothelioma and the occupational asbestos exposure is well known, while few studies have shown a relationship to non-occupational exposures. The aim of this study was to quantify the risk of mesothelioma death associated with neighborhood asbestos exposures due to a large-scale asbestos-cement (AC) plant in Amagasaki, Japan, adjusting properly considerable risk factors including occupational exposures. We conducted a nested case-control study in which a fixed population of 143,929 residents who had been living in Amagasaki City between 1975 and 2002 were followed from 2002 to 2015. All 133 cases and 403 matched controls were interviewed about their occupational, domestic, household, and neighborhood asbestos exposures. Odds ratios (ORs) for mesothelioma death associated with the neighborhood exposure were estimated by a conditional logistic-regression model. For quantitative assessments for neighborhood exposure, we adopted cumulative indices for individuals' residential histories at each residence-specific asbestos concentration multiplied by the duration during the potential exposure period of 1957-1975 (crocidolite). We observed an increasing, dose-dependent risk of mesothelioma death associated with the neighborhood exposure, demonstrating that ORs in the highest quintile category were 21.4 (95% CI: 5.8 - 79.2) for all, 23.7 (95% CI: 3.8 -147.2) for males, and 26.0 (95% CI: 2.8 - 237.5) for females compared to the lowest quintile, respectively. A quantitative assessment for risk of mesothelioma deaths, adjusting for occupational and the other non-occupational exposures separately, showed a dose-dependent association with the neighborhood exposure and no substantial gender differences in magnitude.
    Keywords:  asbestos; mesothelioma; neighborhood exposure; non- occupational exposure; residential history
    DOI:  https://doi.org/10.1111/cas.15802
  8. Cancer Treat Rev. 2023 Mar 17. pii: S0305-7372(23)00033-6. [Epub ahead of print]116 102542
    Comprehensive evaluation of surrogate endpoints to predict overall survival in trials with PD1/PD-L1 immune checkpoint inhibitors plus chemotherapy.
    Guillermo Villacampa, Pablo Cresta Morgado, Victor Navarro, Cristina Viaplana, Rodrigo Dienstmann.
       BACKGROUND: PD1/PD-L1 immune checkpoint inhibitors (ICI) have revolutionized cancer treatment. Although there is controversy about the accuracy of surrogate endpoints in the ICI setting to predict overall survival (OS), these endpoints are commonly used in confirmatory trials. Here we aimed to explore the validity of classical and novel surrogate endpoints in randomised controlled trials (RCT) that combine ICI plus chemotherapy (CT) in the first-line setting.
    MATERIAL AND METHODS: A systematic review was conducted to identify RCT investigating anti-PD1/PD-L1 drugs plus CT versus CT alone. We performed (i) arm-level analysis to evaluate predictors of median OS (mOS) and (ii) comparison-level analysis for OS hazard ratio (HR) estimations. Linear regression models weighted by trial size were fitted and adjusted R2 values were reported.
    RESULTS: Thirty-nine RCTs involving 22,341 patients met the inclusion criteria (17 non-small cell lung, 9 gastroesophageal and 13 in other cancers) with ten different ICI under study. Overall, ICI plus CT improved OS (HR = 0.76; 95%CI: 0.73-0.80). In the arm-level analysis, the best mOS prediction was obtained with a new endpoint that combines median duration of response and ORR (mDoR-ORR) and with median PFS (R2 = 0.5 both). In the comparison-level analysis, PFS HR showed a moderate association with OS HR (R2 = 0.52). Early OS read-outs were highly associated with final OS outcomes (R2 = 0.80).
    CONCLUSIONS: The association between surrogate endpoints and OS in first-line RCT combining anti-PD1/PD-L1 and CT is moderate-low. Early OS read-outs showed a good association with final OS HR while the mDOR-ORR endpoint could help to better design confirmatory trials after single-arm phase II trials.
    Keywords:  Duration of response; First-line; Immune checkpoint inhibitors; PD1/PD-L1; Surrogate endpoints
    DOI:  https://doi.org/10.1016/j.ctrv.2023.102542
  9. Exp Mol Med. 2023 Apr 03.
    BAP1 as a guardian of genome stability: implications in human cancer.
    Jongbum Kwon, Daye Lee, Shin-Ai Lee.
      BAP1 is a ubiquitin C-terminal hydrolase domain-containing deubiquitinase with a wide array of biological activities. Studies in which advanced sequencing technologies were used have uncovered a link between BAP1 and human cancer. Somatic and germline mutations of the BAP1 gene have been identified in multiple human cancers, with a particularly high frequency in mesothelioma, uveal melanoma and clear cell renal cell carcinoma. BAP1 cancer syndrome highlights that all carriers of inherited BAP1-inactivating mutations develop at least one and often multiple cancers with high penetrance during their lifetime. These findings, together with substantial evidence indicating the involvement of BAP1 in many cancer-related biological activities, strongly suggest that BAP1 functions as a tumor suppressor. Nonetheless, the mechanisms that account for the tumor suppressor function of BAP1 have only begun to be elucidated. Recently, the roles of BAP1 in genome stability and apoptosis have drawn considerable attention, and they are compelling candidates for key mechanistic factors. In this review, we focus on genome stability and summarize the details of the cellular and molecular functions of BAP1 in DNA repair and replication, which are crucial for genome integrity, and discuss the implications for BAP1-associated cancer and relevant therapeutic strategies. We also highlight some unresolved issues and potential future research directions.
    DOI:  https://doi.org/10.1038/s12276-023-00979-1
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