Evolution of Genomic and T-cell Repertoire Heterogeneity of Malignant Pleural Mesothelioma Under Dasatinib Treatment

Chen, Runzhe; Lee, Won‐Chul; Fujimoto, Junya; Li, Jun; Hu, Xin; Mehran, Reza J.; Rice, David C.; Swisher, Stephen G.; Sepesi, Boris; Tran, Hai T.; Chow, Chi-Wan; Little, Latasha; Gumbs, Curtis; Haymaker, Cara; Heymach, John V.; Wistuba, Ignacio I.; Lee, J. Jack; Futreal, P. Andrew; Zhang, Jianhua; Reuben, Alexandre; Tsao, Anne S.

doi:10.1158/1078-0432.ccr-20-1767

Cited by 19 publications

(27 citation statements)

References 61 publications

(45 reference statements)

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“…In this study, we found that inhibitors selectively targeting BCR-ABL, such as Dasatinib, preferentially inhibit LATS1/2 -mutant MPM cells. More importantly, Dasatinib and other clinically approved BCR-ABL inhibitors have been shown to enhance T-cell-mediated immune response in various cancer types [ 9 , 39 , 81 ], including MPM [ 81 ]. Based on multi-region whole-exome and T-cell receptor (TCR) sequencing, Chen et al [ 81 ] evaluated the evolution of T-cell repertoire heterogeneity of MPM under Dasatinib treatment, demonstrating a highly heterogeneous TCR repertoire within MPM samples.…”

Section: Discussionmentioning

confidence: 99%

“…More importantly, Dasatinib and other clinically approved BCR-ABL inhibitors have been shown to enhance T-cell-mediated immune response in various cancer types [ 9 , 39 , 81 ], including MPM [ 81 ]. Based on multi-region whole-exome and T-cell receptor (TCR) sequencing, Chen et al [ 81 ] evaluated the evolution of T-cell repertoire heterogeneity of MPM under Dasatinib treatment, demonstrating a highly heterogeneous TCR repertoire within MPM samples. Intriguingly, the evidence also showed that, compared to pre-treatment tumors, Dasatinib treatment induced a significant increase in T-cell clonality, and patients with higher T-cell clonality and more homogeneous T-cell repertoire after treatment had significantly better survival.…”

Section: Discussionmentioning

confidence: 99%

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NF2 and Canonical Hippo-YAP Pathway Define Distinct Tumor Subsets Characterized by Different Immune Deficiency and Treatment Implications in Human Pleural Mesothelioma

Yang

Hall

Sun

et al. 2021

Cancers

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(1) Inactivation of the tumor suppressor NF2 is believed to play a major role in the pathogenesis of malignant pleural mesothelioma (MPM) by deregulating the Hippo-YAP signaling pathway. However, NF2 has functions beyond regulation of the Hippo pathway, raising the possibility that NF2 contributes to MPM via Hippo-independent mechanisms. (2) We performed weighted gene co-expression analysis (WGCNA) in transcriptomic and proteomic datasets obtained from The Cancer Gene Atlas (TCGA) MPM cohort to identify clusters of co-expressed genes highly correlated with NF2 and phospho (p)-YAP protein, surrogate markers of active Hippo signaling and YAP inactivation. The potential targets are experimentally validated using a cell viability assay. (3) MPM tumors with NF2 loss-of-function are not associated with changes in p-YAP level nor YAP/TAZ activity score, but are characterized by a deficient B-cell receptor (BCR) signaling pathway. Conversely, MPM tumors with YAP activation display exhausted CD8 T-cell-mediated immunity together with significantly upregulated PD-L1, which is validated in an independent MPM cohort, suggesting a potential benefit of immune-checkpoint inhibitors (ICI) in this patient subset. In support of this, mutations in core Hippo signaling components including LATS2, but not NF2, are independently associated with better overall survival in response to ICI in patients. Additionally, based on cancer cell line models, we show that MPM cells with a high Hippo-YAP activity are particularly sensitive to inhibitors of BCR-ABL/SRC, stratifying a unique MPM patient subset that may benefit from BCR-ABL/SRC therapies. Furthermore, we observe that NF2 physically interacts with a considerable number of proteins that are not involved in the canonical Hippo-YAP pathway, providing a possible explanation for its Hippo-independent role in MPM. Finally, survival analyses show that YAP/TAZ scores together with p-YAP protein level, but not NF2, predict the prognosis of MPM patients. (4) NF2 loss-of-function and dysregulated Hippo-YAP pathway define distinct MPM subsets that differ in their molecular features and prognosis, which has important clinical implications for precision oncology in MPM patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

NF2 and Canonical Hippo-YAP Pathway Define Distinct Tumor Subsets Characterized by Different Immune Deficiency and Treatment Implications in Human Pleural Mesothelioma

Yang

Hall

Sun

et al. 2021

Cancers

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“…Therefore, cancer cells with enhanced CD73 activity might be sensitive to dasatinib treatment, but resistant to pan-HDAC inhibitors. Regarding this, we and others have previously shown that dasatinib not only inhibits cancer cells but also modulates the tumor immune microenvironment and enhances the efficacy of ICIs [ 133 , 134 , 135 ]. Others have shown that dasatinib effectively blocks TGFβ-induced expression of transcription factors promoting EMT and may be a novel therapeutic option in pancreatic and prostate cancer [ 136 ] and pulmonary sarcomatoid carcinoma, a rare and deadly form of NSCLC [ 137 ].…”

Section: Cd73 and Drug Repurposingmentioning

confidence: 98%

CD73, Tumor Plasticity and Immune Evasion in Solid Cancers

Yang

Yao

Davis

et al. 2021

Cancers

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Regulatory networks controlling cellular plasticity, important during early development, can re-emerge after tissue injury and premalignant transformation. One such regulatory molecule is the cell surface ectoenzyme ecto-5′-nucleotidase that hydrolyzes the conversion of extracellular adenosine monophosphate to adenosine (eADO). Ecto-5′-nucleotidase (NT5E) or cluster of differentiation 73 (CD73), is an enzyme that is encoded by NT5E in humans. In normal tissue, CD73-mediated generation of eADO has important pleiotropic functions ranging from the promotion of cell growth and survival, to potent immunosuppression mediated through purinergic G protein-coupled adenosine receptors. Importantly, tumors also utilize several mechanisms mediated by CD73 to resist therapeutics and in particular, evade the host immune system, leading to undesired resistance to targeted therapy and immunotherapy. Tumor cell CD73 upregulation is associated with worse clinical outcomes in a variety of cancers. Emerging evidence indicates a link between tumor cell stemness with a limited host anti-tumor immune response. In this review, we provide an overview of a growing body of evidence supporting the pro-tumorigenic role of CD73 and adenosine signaling. We also discuss data that support a link between CD73 expression and tumor plasticity, contributing to dissemination as well as treatment resistance. Collectively, targeting CD73 may represent a novel treatment approach for solid cancers.

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“…A multi-region, longitudinal whole exome and T-cell receptor sequencing analysis was conducted on 69 specimens from nine MPM tumors before and after dasatinib treatment. It was found that mutation profile among sites was relatively homogeneous (>80% concordance), but T-cell clonality varied widely particularly after treatment (40).…”

Section: Genetic and Epigenetic Effects On The Immune Responsementioning

confidence: 99%

Immune Microenvironment and Genetics in Malignant Pleural Mesothelioma

2021

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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.

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Evolution of Genomic and T-cell Repertoire Heterogeneity of Malignant Pleural Mesothelioma Under Dasatinib Treatment

Cited by 19 publications

References 61 publications

NF2 and Canonical Hippo-YAP Pathway Define Distinct Tumor Subsets Characterized by Different Immune Deficiency and Treatment Implications in Human Pleural Mesothelioma

NF2 and Canonical Hippo-YAP Pathway Define Distinct Tumor Subsets Characterized by Different Immune Deficiency and Treatment Implications in Human Pleural Mesothelioma

CD73, Tumor Plasticity and Immune Evasion in Solid Cancers

Immune Microenvironment and Genetics in Malignant Pleural Mesothelioma

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