Matter of TIME: the tumor-immune microenvironment of mesothelioma and implications for checkpoint blockade efficacy

Harber, James; Kamata, Tamihiro; Pritchard, Catrin; Fennell, Dean A.

doi:10.1136/jitc-2021-003032

Cited by 25 publications

(20 citation statements)

References 122 publications

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“…Our study also found that TMB was positively correlated to the ferroptosis score. The previous studies have reported that TMB could serve as a latent biomarker of the response to immunotherapy using checkpoint inhibitors in multiple cancers such as lung cancer and mesothelioma ( Harber et al, 2021 ; Sholl, 2021 ). Therefore, we would like to figure out whether the ferroptosis score could predict the response to immunotherapy and guide clinical treatment strategies.…”

Section: Discussionmentioning

confidence: 99%

Ferroptosis Patterns and Tumor Microenvironment Infiltration Characterization in Bladder Cancer

Xia

Sun

Liu

et al. 2022

Front. Cell Dev. Biol.

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Background: Ferroptosis is a unique iron-dependent form of cell death and bladder cancer (BCa) is one of the top ten most common cancer types in the world. However, the role of ferroptosis in shaping the tumor microenvironment and influencing tumor clinicopathological features remains unknown.Methods: Using the data downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we comprehensively evaluated the ferroptosis patterns of 570 BCa samples based on 234 validated ferroptosis genes reported in the FerrDb database and systematically correlated these ferroptosis patterns with tumor microenvironment (TME) cell-infiltrating characteristics. The ferroptosis score was constructed to quantify ferroptosis patterns of individuals using principal component analysis (PCA) algorithms.Results: Four distinct ferroptosis patterns and two gene clusters were finally determined. Significant differences in clinical characteristics and the prognosis of patients were found among different ferroptosis patterns and gene clusters, so were in the mRNA transcriptome and the landscape of TME immune cell infiltration. We also established a set of scoring system to quantify the ferroptosis pattern of individual patients with BCa named the ferroptosis score, which was discovered to tightly interact with clinical signatures such as the TNM category and tumor grade and could predict the prognosis of patients with BCa. Moreover, tumor mutation burden (TMB) was positively correlated to the ferroptosis score, and the low ferroptosis score was related to a better response to immunotherapy using PD-1 blockade. Finally, we also found there existed a positive correlation between the sensitivity to cisplatin chemotherapy and ferroptosis score.Conclusions: Our work demonstrated and interpreted the complicated regulation mechanisms of ferroptosis on the tumor microenvironment and that better understanding and evaluating ferroptosis patterns could be helpful in guiding the clinical therapeutic strategy and improving the prognosis of patients with BCa.

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Section: Discussionmentioning

confidence: 99%

Ferroptosis Patterns and Tumor Microenvironment Infiltration Characterization in Bladder Cancer

Xia

Sun

Liu

et al. 2022

Front. Cell Dev. Biol.

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“…For decades, no progress whatsoever has been made in MPM, and many trials have failed to demonstrate the efficacy of new treatments [71] . A better knowledge of tumor biology and its interactions with immune cells and tumor microenvironment has recently led to a therapeutic paradigm shift in MPM, with the entrance to the clinic of the first chemotherapy-free regimen based on the association of nivolumab plus ipilimumab [10,72] .…”

Section: Discussionmentioning

confidence: 99%

Immunotherapy in malignant pleural mesothelioma: a long story ended in success

Bongiovanni¹,

Frassoldati²,

Calabrò³

2022

J Cancer Metastasis Treat

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Malignant pleural mesothelioma (MPM) is an aggressive and rare disease, mainly due to asbestos exposure, characterized by a poor prognosis. For almost two decades, platinum-based chemotherapy has been the only approved therapeutic regimen for first-line MPM, with an overall survival of 12 months. In the last years, the therapeutic scenario of different tumor types, including MPM, has dramatically changed due to immune checkpoint inhibition. The promising results of this approach have promoted new efforts into clinical research, and many trials investigating novel therapeutic combinations are currently ongoing. The aim of the present review is to provide a comprehensive overview of the most promising immunotherapeutic-based strategies currently under investigation for advanced MPM.

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“…To conclude, our study supports further clinical evaluation of CDK4/6i for the treatment of pleural mesotheliomas including in various combinations with the standard therapies. Most MPM patients could respond to CDK4/6i, which may not only arrest tumor growth but also help to convert the mesotheliomas that are rarely immunologically 'cold' but more frequently in intermediate inflammatory states (114), into 'hot' tumors responsive to immunotherapy. Nevertheless, a minority of intrinsically CDK4/6i insensitive tumors lacking CDK4 phosphorylation might have to be identified.…”

Section: Discussionmentioning

confidence: 99%

Preclinical evaluation of CDK4 phosphorylation predicts high sensitivity of malignant pleural mesotheliomas to CDK4/6 inhibition

Paternot

Raspé

Meiller

et al. 2022

Preprint

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Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. In this study, we evaluated the impact of CDK4/6 inhibition by palbociclib in a panel of 28 MPM cell lines, including 19 patient-derived cell lines, using a variety of approaches including RNA-sequencing. Palbociclib used alone sufficed to strongly and durably inhibit the proliferation of 23 MPM cell lines, indicating a unique sensitivity of MPM to CDK4/6 inhibition. Importantly, insensitivity to palbociclib was mostly explained by the lack of active T172-phosphorylated CDK4. This was associated with the high p16INK4A (CDKN2A) levels that accompany RB1 defects or inactivation, and also (unexpectedly) cyclin E1 over-expression in the presence of wild-type RB1. Prolonged treatment with palbociclib irreversibly inhibited proliferation despite re-induction of cell cycle genes upon drug washout. A senescence-associated secretory phenotype including various potentially immunogenic components was also irreversibly induced. Phosphorylated CDK4 was detected in 80% of 47 MPM tumors indicating their intrinsic sensitivity to CDK4/6 inhibitors. The absence of this phosphorylation in some highly proliferative MPM tumors was linked to partial deletions of RB1, leading to very high p16 (CDKN2A) expression. Our study strongly supports the clinical evaluation of CDK4/6 inhibitory drugs for MPM treatment, in monotherapy or combination therapy.

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Matter of TIME: the tumor-immune microenvironment of mesothelioma and implications for checkpoint blockade efficacy

Cited by 25 publications

References 122 publications

Ferroptosis Patterns and Tumor Microenvironment Infiltration Characterization in Bladder Cancer

Ferroptosis Patterns and Tumor Microenvironment Infiltration Characterization in Bladder Cancer

Immunotherapy in malignant pleural mesothelioma: a long story ended in success

Preclinical evaluation of CDK4 phosphorylation predicts high sensitivity of malignant pleural mesotheliomas to CDK4/6 inhibition

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