Comprehensive Analysis of Cuproptosis-Related Genes in Immune Infiltration and Prognosis in Melanoma

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Abstract

Skin cutaneous melanoma (SKCM, hereafter referred to as melanoma) is the most lethal skin cancer with increasing incidence. Regulated cell death plays an important role in tumorigenesis and serves as an important target for almost all treatment strategies. Cuproptosis is the most recently identified copper-dependent regulated cell death form that relies on mitochondria respiration. However, its role in tumorigenesis remains unknown. The correlation of cuproptosis-related genes with tumor prognosis is far to be understood, either. In the present study, we explored the correlation between cuproptosis-related genes with the prognosis of melanoma by accessing and analyzing a public database and found 11 out 12 genes were upregulated in melanoma tissues and three genes (LIPT1, PDHA1, and SLC31A1) have predictive value for the prognosis. The subgroup of melanoma patients with higher cuproptosis-related gene expression showed longer overall survival than those with lower gene expression. We chose LIPT1 for further exploration. LIPT1 expression was increased in melanoma biopsies and was an independent favorable prognostic indicator for melanoma patients. Moreover, LIPT1 expression was positively correlated with PD-L1 expression and negatively associated with Treg cell infiltration. The melanoma patients with higher LIPT1 expression showed longer overall survival than those with lower LIPT1 expression after receiving immunotherapy, indicating the prognostic predictive value of LIPT1. Finally, a pan-cancer analysis indicated that LIPT1 was differentially expressed in diverse cancers as compared to normal tissues and correlated with the expression of multiple immune checkpoints, especially PD-L1. It could serve as a favorable prognosis indicator in some cancer types. In conclusion, our study demonstrated the prognostic value of cuproptosis-related genes, especially LIPT1, in melanoma, and revealed the correlation between LIPT1 expression and immune infiltration in melanoma, thus providing new clues on the prognostic assessment of melanoma patients and providing a new target for the immunotherapy of melanoma.

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Most cited references 78

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Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

Suzy Torti, Donna D. Zhang, K.A. Woerpel … (2019)

Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.

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IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade

Mark Ayers, Jared Lunceford, Michael Nebozhyn … (2017)

Programmed death-1–directed (PD-1–directed) immune checkpoint blockade results in durable antitumor activity in many advanced malignancies. Recent studies suggest that IFN-γ is a critical driver of programmed death ligand-1 (PD-L1) expression in cancer and host cells, and baseline intratumoral T cell infiltration may improve response likelihood to anti–PD-1 therapies, including pembrolizumab. However, whether quantifying T cell–inflamed microenvironment is a useful pan-tumor determinant of PD-1–directed therapy response has not been rigorously evaluated. Here, we analyzed gene expression profiles (GEPs) using RNA from baseline tumor samples of pembrolizumab-treated patients. We identified immune-related signatures correlating with clinical benefit using a learn-and-confirm paradigm based on data from different clinical studies of pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually defining a pan-tumor T cell–inflamed GEP in 220 patients with 9 cancers. Predictive value was independently confirmed and compared with that of PD-L1 immunohistochemistry in 96 patients with head and neck squamous cell carcinoma. The T cell–inflamed GEP contained IFN-γ–responsive genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance, and these features were necessary, but not always sufficient, for clinical benefit. The T cell–inflamed GEP has been developed into a clinical-grade assay that is currently being evaluated in ongoing pembrolizumab trials.

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Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients.

Roy S. Herbst, Jean-Charles Soria, Marcin Kowanetz … (2014)

The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish cancer cells from their normal counterparts, allowing tumours to be recognized as foreign by the immune system. However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironment. Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and immune cells, plays an important part in blocking the 'cancer immunity cycle' by binding programmed death-1 (PD-1) and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumour cell killing. The PD-L1-PD-1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections. Blocking PD-L1 should therefore enhance anticancer immunity, but little is known about predictive factors of efficacy. This study was designed to evaluate the safety, activity and biomarkers of PD-L1 inhibition using the engineered humanized antibody MPDL3280A. Here we show that across multiple cancer types, responses (as evaluated by Response Evaluation Criteria in Solid Tumours, version 1.1) were observed in patients with tumours expressing high levels of PD-L1, especially when PD-L1 was expressed by tumour-infiltrating immune cells. Furthermore, responses were associated with T-helper type 1 (TH1) gene expression, CTLA4 expression and the absence of fractalkine (CX3CL1) in baseline tumour specimens. Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment.

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Author and article information

Contributors

Haozhen Lv: URI : https://loop.frontiersin.org/people/1655968/overview

Xiao Liu: URI : https://loop.frontiersin.org/people/1379140/overview

Xuanhao Zeng: URI : https://loop.frontiersin.org/people/584391/overview

Yating Liu: URI : https://loop.frontiersin.org/people/1655464/overview

Canjing Zhang: URI : https://loop.frontiersin.org/people/1572587/overview

Qi Zhang: URI : https://loop.frontiersin.org/people/1161852/overview

Jinhua Xu: URI : https://loop.frontiersin.org/people/999150/overview

Journal

Journal ID (nlm-ta): Front Pharmacol

Journal ID (iso-abbrev): Front Pharmacol

Journal ID (publisher-id): Front. Pharmacol.

Title: Frontiers in Pharmacology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1663-9812

Publication date (Electronic): 28 June 2022

Publication date Collection: 2022

Volume: 13

Electronic Location Identifier: 930041

Affiliations

[1] ¹ Department of Dermatology , Huashan Hospital , Fudan University , Shanghai, China

[2] ² Institutes of Biomedical Sciences , Fudan University , Shanghai, China

[3] ³ Shanghai Institute of Dermatology , Shanghai, China

Author notes

Edited by: Zhijie Xu, Central South University, China

Reviewed by: Weimin Shi, Shanghai General Hospital, China

Zizhao Xu, The University of the Pacific, United States

*Correspondence: Qi Zhang, chyoki@ 123456hotmail.com ; Jinhua Xu, jinhuaxu@ 123456fudan.edu.cn

[ † ]

These authors have contributed equally to this work

This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Pharmacology

Article

Publisher ID: 930041

DOI: 10.3389/fphar.2022.930041

PMC ID: 9273972

PubMed ID: 35837286

SO-VID: 22285b1f-c2c0-4cb1-90cb-23611102b5c4

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 27 April 2022

Date accepted : 19 May 2022

Funding

Funded by: National Natural Science Foundation of China Science and Technology Commission of Shanghai Municipality , doi 10.13039/501100001809 10.13039/501100003399;

Comprehensive Analysis of Cuproptosis-Related Genes in Immune Infiltration and Prognosis in Melanoma

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Karger: Oncology

Most cited references 78

Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade

Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients.

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