Establishment and validation of a novel risk model based on CD8T cell marker genes to predict prognosis in thyroid cancer by integrated analysis of single-cell and bulk RNA-sequencing

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Abstract

Papillary thyroid cancer (PTC) is a histological type of thyroid cancer, and CD8T is important for the immune response. The single-cell RNA data were acquired from Gene Expression Omnibus. SingleR package was used for cluster identification, and CellChat was exploited to evaluate the interaction among several cell types. Bulk RNA data obtained from the cancer genome atlas were used for determination of prognosis using Kaplan–Meier and Receiver Operating Characteristic curve. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis were applied for assessment of function enrichment. The drug sensitivity was calculated in Gene Set Cancer Analysis. The regulatory network was constructed by STRING and Cytoscape. We identified 23 cell clusters and 10 cell types. Cell communication results showed CD8T cell was vital among all immune cell types. Enrichment analysis found the marker genes of CD8T cell was enriched in some signal pathways related to tumor development. Overall, FAM107B and TUBA4A were considered as hub genes and used to construct a risk model. Most immune checkpoint expressions were upregulated in tumor group. Tumor mutation burden results indicated that prognosis of PTC was not related to the mutation of hub genes. Drug sensitivity analysis showed some drugs could be effectively used for the treatment of PTC, and regulatory network identified some targets for the immunotherapy. A 2-gene model of PTC was developed based on the single-cell RNA and bulk RNA data. Besides, we found CD8T was essential for the immune response in PTC.

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Most cited references 42

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Thyroid cancer

Maria Cabanillas, David McFadden, Cosimo Durante (2016)

Thyroid cancer is the fifth most common cancer in women in the USA, and an estimated over 62 000 new cases occurred in men and women in 2015. The incidence continues to rise worldwide. Differentiated thyroid cancer is the most frequent subtype of thyroid cancer and in most patients the standard treatment (surgery followed by either radioactive iodine or observation) is effective. Patients with other, more rare subtypes of thyroid cancer-medullary and anaplastic-are ideally treated by physicians with experience managing these malignancies. Targeted treatments that are approved for differentiated and medullary thyroid cancers have prolonged progression-free survival, but these drugs are not curative and therefore are reserved for patients with progressive or symptomatic disease.

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Deciphering miRNAs’ Action through miRNA Editing

Marta Correia de Sousa, Monika Gjorgjieva, Dobrochna Dolicka … (2019)

MicroRNAs (miRNAs) are small non-coding RNAs with the capability of modulating gene expression at the post-transcriptional level either by inhibiting messenger RNA (mRNA) translation or by promoting mRNA degradation. The outcome of a myriad of physiological processes and pathologies, including cancer, cardiovascular and metabolic diseases, relies highly on miRNAs. However, deciphering the precise roles of specific miRNAs in these pathophysiological contexts is challenging due to the high levels of complexity of their actions. Indeed, regulation of mRNA expression by miRNAs is frequently cell/organ specific; highly dependent on the stress and metabolic status of the organism; and often poorly correlated with miRNA expression levels. Such biological features of miRNAs suggest that various regulatory mechanisms control not only their expression, but also their activity and/or bioavailability. Several mechanisms have been described to modulate miRNA action, including genetic polymorphisms, methylation of miRNA promoters, asymmetric miRNA strand selection, interactions with RNA-binding proteins (RBPs) or other coding/non-coding RNAs. Moreover, nucleotide modifications (A-to-I or C-to-U) within the miRNA sequences at different stages of their maturation are also critical for their functionality. This regulatory mechanism called “RNA editing” involves specific enzymes of the adenosine/cytidine deaminase family, which trigger single nucleotide changes in primary miRNAs. These nucleotide modifications greatly influence a miRNA’s stability, maturation and activity by changing its specificity towards target mRNAs. Understanding how editing events impact miRNA’s ability to regulate stress responses in cells and organs, or the development of specific pathologies, e.g., metabolic diseases or cancer, should not only deepen our knowledge of molecular mechanisms underlying complex diseases, but can also facilitate the design of new therapeutic approaches based on miRNA targeting. Herein, we will discuss the current knowledge on miRNA editing and how this mechanism regulates miRNA biogenesis and activity.

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TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion

Hyungseok Seo, Joyce Chen, Edahí González-Avalos … (2019)

T cells expressing chimeric antigen receptors (CAR T cells) have shown impressive therapeutic efficacy against leukemias and lymphomas. However, they have not been as effective against solid tumors because they become hyporesponsive (“exhausted” or “dysfunctional”) within the tumor microenvironment, with decreased cytokine production and increased expression of several inhibitory surface receptors. Here we define a transcriptional network that mediates CD8 + T cell exhaustion. We show that the high-mobility group (HMG)-box transcription factors TOX and TOX2, as well as members of the NR4A family of nuclear receptors, are targets of the calcium/calcineurin-regulated transcription factor NFAT, even in the absence of its partner AP-1 (FOS-JUN). Using a previously established CAR T cell model, we show that TOX and TOX2 are highly induced in CD8 + CAR + PD-1 high TIM3 high (“exhausted”) tumor-infiltrating lymphocytes (CAR TILs), and CAR TILs deficient in both TOX and TOX2 ( Tox DKO) are more effective than wild-type (WT), TOX-deficient, or TOX2-deficient CAR TILs in suppressing tumor growth and prolonging survival of tumor-bearing mice. Like NR4A-deficient CAR TILs, Tox DKO CAR TILs show increased cytokine expression, decreased expression of inhibitory receptors, and increased accessibility of regions enriched for motifs that bind activation-associated nuclear factor κB (NFκB) and basic region-leucine zipper (bZIP) transcription factors. These data indicate that Tox and Nr4a transcription factors are critical for the transcriptional program of CD8 + T cell exhaustion downstream of NFAT. We provide evidence for positive regulation of NR4A by TOX and of TOX by NR4A, and suggest that disruption of TOX and NR4A expression or activity could be promising strategies for cancer immunotherapy.

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Author and article information

Contributors

Jian Du

Cheng-Fei Song

Shu Wang

Yu-Cheng Tan

Journal

Journal ID (nlm-ta): Medicine (Baltimore)

Journal ID (iso-abbrev): Medicine (Baltimore)

Journal ID (publisher-id): MD

Title: Medicine

Publisher: Lippincott Williams & Wilkins (Hagerstown, MD )

ISSN (Print): 0025-7974

ISSN (Electronic): 1536-5964

Publication date Collection: 20 October 2023

Publication date (Electronic): 20 October 2023

Volume: 102

Issue: 42

Electronic Location Identifier: e35192

Affiliations

[a ] General Surgery Department, General Hospital of Fushun Mining Bureau of Liaoning Health Industry Group, Fushun, Liaoning, China.

Author notes

[* ] Correspondence: Jiang Wang, General Surgery Department, General Hospital of Fushun Mining Bureau of Liaoning Health Industry Group, No.24, Central Street, Xinfu District, Fushun City 113000, Liaoning Province, China (e-mail: wangjiangwj1991@ 123456163.com ).

Author information

Jiang Wang https://orcid.org/0009-0008-9688-4416

Article

Accession ID: 00085

DOI: 10.1097/MD.0000000000035192

PMC ID: 10589543

PubMed ID: 37861558

SO-VID: c315f26e-863d-4b8e-b454-b9ad8fa6101d

License:

This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 12 June 2023

Date received : 07 August 2023

Date accepted : 22 August 2023

Custom metadata

OPEN-ACCESS TRUE

SDC T

Keywords: bulk rna,cd8t,papillary thyroid cancer,prognosis,single-cell rna

Data availability:

Keywords: bulk rna, cd8t, papillary thyroid cancer, prognosis, single-cell rna

Establishment and validation of a novel risk model based on CD8T cell marker genes to predict prognosis in thyroid cancer by integrated analysis of single-cell and bulk RNA-sequencing

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