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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., Competing Interests: Beyond the scope of this study, AS participated to clinical trials and expert boards with Amphera, AstraZeneca, BMS, MSD, Regeneron/Sanofi, Roche and Trizell. VH declares consultancy fees from AstraZeneca and Chiesi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Willems, Scherpereel, Wasielewski, Raskin, Brossel, Fontaine, Grégoire, Halkin, Jamakhani, Heinen, Louis, Duysinx, Hamaidia and Willems.)

Simple Summary: Tumor-associated macrophages and monocyte myeloid-derived immunosuppressive cells are associated with bad prognosis in malignant pleural mesothelioma (MPM). This study shows that peripheral blood monocytes can, nevertheless, be cytotoxic for MPM tumor cells. This cytotoxic activity that involves direct cell-to-cell contact can be improved with a lysine deacetylase inhibitor (VPA), opening new prospects for further improvement of still unsatisfactory MPM therapies. The composition of the tumor microenvironment (TME) mediates the outcome of chemo- and immunotherapies in malignant pleural mesothelioma (MPM). Tumor-associated macrophages (TAMs) and monocyte myeloid-derived immunosuppressive cells (M-MDSCs) constitute a major fraction of the TME. As central cells of the innate immune system, monocytes exert well-characterized functions of phagocytosis, cytokine production, and antibody-dependent cell-mediated cytotoxicity (ADCC). The objective of this study was to evaluate the ability of monocytes to exert a direct cytotoxicity by cell-to-cell contact with MPM cells. The experimental model is based on cocultures between human blood-derived monocytes sorted by negative selection and mesothelioma cell lines. Data show (i) that blood-derived human monocytes induce tumor cell death by direct cell-to-cell contact, (ii) that VPA is a pharmacological enhancer of this cytotoxic activity, (iii) that VPA increases monocyte migration and their aggregation with MPM cells, and (iv) that the molecular mechanisms behind VPA modulation of monocytes involve a downregulation of the membrane receptors associated with the M2 phenotype, i.e., CD163, CD206, and CD209. These conclusions, thus, broaden our understanding about the molecular mechanisms involved in immunosurveillance of the tumor microenvironment and open new prospects for further improvement of still unsatisfactory MPM therapies [ABSTRACT FROM AUTHOR]

Simple Summary: 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 malignant mesothelioma (MM), tumor development is nevertheless characterized by a low mutation rate despite major structural chromosomal rearrangements driving oncogenesis. In this paper, we propose a paradigm 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. 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. [ABSTRACT FROM AUTHOR]

Background: There is no standard chemotherapy for refractory or relapsing malignant pleural mesothelioma (MPM). Our previous reports nevertheless indicated that a combination of an anthracycline (doxorubicin) and a lysine deacetylase inhibitor (valproic acid, VPA) synergize to induce the apoptosis of MPM cells and reduce tumor growth in mouse models. A Phase I/II clinical trial indicated that this regimen is a promising therapeutic option for a proportion of MPM patients. Methods: The transcriptomes of mesothelioma cells were compared after Illumina HiSeq 4000 sequencing. The expression of differentially expressed genes was inhibited by RNA interference. Apoptosis was determined by cell cycle analysis and Annexin V/7-AAD labeling. Protein expression was assessed by immunoblotting. Preclinical efficacy was evaluated in BALB/c and NOD-SCID mice. Results: To understand the mechanisms involved in chemoresistance, the transcriptomes of two MPM cell lines displaying different responses to VPA-doxorubicin were compared. Among the differentially expressed genes, transforming growth factor alpha (TGFα) was associated with resistance to this regimen. The silencing of TGFα by RNA interference correlated with a significant increase in apoptosis, whereas the overexpression of TGFα desensitized MPM cells to the apoptosis induced by VPA and doxorubicin. The multi-targeted inhibition of histone deacetylase (HDAC), HER2 and TGFα receptor (epidermal growth factor receptor/EGFR) improved treatment efficacy in vitro and reduced tumor growth in two MPM mouse models. Finally, TGFα expression but not EGFR correlated with patient survival. Conclusions: Our data show that TGFα but not its receptor EGFR is a key factor in resistance to MPM chemotherapy. This observation may contribute to casting light on the promising but still controversial role of EGFR signaling in MPM therapy. [ABSTRACT FROM AUTHOR]