Epigenetic Alterations and Biomarkers for Immune Checkpoint Inhibitors–Current Standards and Future Perspectives in Malignant Pleural Mesothelioma Treatment

Abstract

Malignant pleural mesothelioma (MPM) is strongly associated with occupational or environmental asbestos exposure and arises from neoplastic transformation of mesothelial cells in the pleural cavity. The only standard initial treatment for unresectable MPM is combination chemotherapy with cisplatin (CDDP) and pemetrexed (PEM). Further, CDDP/PEM is the only approved regimen with evidence of prolonged overall survival (OS), although the median OS for patients treated with this regimen is only 12 months after diagnosis. Thus, the development of new therapeutic strategies has been investigated for approximately 20 years. In contrast to recent advances in personalized lung cancer therapies, diagnostic and prognostic biomarker research has just started in mesothelioma. Epigenetic alterations include DNA methylation, histone modifications, and other chromatin-remodeling events. These processes are involved in numerous cellular processes including differentiation, development, and tumorigenesis. Epigenetic modifications play an important role in gene expression and regulation related to malignant MPM phenotypes and histological subtypes. An immune checkpoint PD-1 inhibitor, nivolumab, was approved as second-line therapy for patients who had failed initial chemotherapy, based on the results of the MERIT study. Various clinical immunotherapy trials are ongoing in patients with advanced MPM. In this review, we describe recent knowledge on epigenetic alterations, which might identify candidate therapeutic targets and immunotherapeutic regimens under development for MPM.

Emerging avenues in immunotherapy for the management of malignant pleural mesothelioma

“…As such PD-L1 remains a contentious biomarker in this sphere, and a significant number of patients exist who whilst being PD-L1 negative, demonstrate ORRs to checkpoint inhibitors. The challenge will be to identify new markers or ways to identify such patients, perhaps using transcriptomic or other approaches [ 53 , 154 – 157 ].…”

Profiles of expressed mutations in single cells reveal subclonal expansion patterns and therapeutic impact of intratumor heterogeneity

“…In fact, overlapped genes that are recurrently mutated in melanomas of R patients are significantly enriched in chromosome organization (including ATR, ZFYVE26, SENP6, NUP153, NUP98) and DNA methylation functions (including SETD2, REST, BCOR, BCOR1). (see Figure 5e for a detailed presentation for commonly and recurrently mutated genes across melanomas, together with function and mutation type information) Recent studies have demonstrated that mutations in DNA repair genes [45] and alteration in histone modification [46] are associated with the efficacy of immune checkpoint blockade therapy .…”

Epigenetic Silencing of Immune-Checkpoint Receptors in Bone Marrow- Infiltrating T Cells in Acute Myeloid Leukemia

“…Dysfunctional and/or immunosuppressive T cells in AML have been previously described, specifically in peripheral blood (14)(15)(16)(17)(18). AML LSCs express different co-stimulatory and coinhibitory ligands, and the efficacy of ICIs is identifiably lower in leukemia than in solid tumors (11).…”

“…Comparably, some IC receptors, including PD-1, were upregulated in CD4 + or CD8 + T cells of AML patients versus healthy controls in the present study. Different studies have demonstrated that aberrant epigenetic alterations, such as histone remodeling and DNA methylation play a crucial role in the dysregulation of ICs during carcinogenesis (14,15,31). In addition, DNA hypomethylating agents (HMAs) such as azacitidine and decitabine upregulate the expression of PD-L1 in solid tumors (16) and AML (17) and thereby dampen the anti-tumor immune response.…”