Circulating cell-free and extracellular vesicles-derived microRNA as prognostic biomarkers in patients with early-stage NSCLC: results from RESTING study

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Abstract

Background

Factors to accurately stratify patients with early-stage non-small cell lung cancer (NSCLC) in different prognostic groups are still needed. This study aims to investigate 1) the prognostic potential of circulating cell-free (CF) and extracellular vesicles (EVs)-derived microRNA (miRNAs), and 2) their added value with respect to known prognostic factors (PFs).

Methods

The RESTING study is a multicentre prospective observational cohort study on resected stage IA-IIIA patients with NSCLC. The primary end-point was disease-free survival (DFS), and the main analyses were carried out separately for CF- and EV-miRNAs. CF- and EV-miRNAs were isolated from plasma, and miRNA-specific libraries were prepared and sequenced. To reach the study aims, three statistical models were specified: one using the miRNA data only (Model 1); one using both miRNAs and known PFs (age, gender, and pathological stage) (Model 2), and one using the PFs alone (Model 3). Five-fold cross-validation (CV) was used to assess the predictive performance of each. Standard Cox regression and elastic net regularized Cox regression were used.

Results

A total of 222 patients were enrolled. The median follow-up time was 26.3 (95% CI 25.4–27.6) months. From Model 1, three CF-miRNAs and 21 EV-miRNAs were associated with DFS. In Model 2, two CF-miRNAs (miR-29c-3p and miR-877-3p) and five EV-miRNAs (miR-181a-2-3p, miR-182-5p, miR-192-5p, miR-532-3p and miR-589-5p) remained associated with DFS. From pathway enrichment analysis, TGF-beta and NOTCH were the most involved pathways.

Conclusion

This study identified promising prognostic CF- and EV-miRNAs that could be used as a non-invasive, cost-effective tool to aid clinical decision-making. However, further evaluation of the obtained miRNAs in an external cohort of patients is warranted.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13046-024-03156-y.

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Most cited references 58

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer.

Peter Goldstraw, Kari Chansky, John Crowley … (2016)

The IASLC Staging and Prognostic Factors Committee has collected a new database of 94,708 cases donated from 35 sources in 16 countries around the globe. This has now been analysed by our statistical partners at Cancer Research And Biostatistics and, in close collaboration with the members of the committee proposals have been developed for the T, N, and M categories of the 8th edition of the TNM Classification for lung cancer due to be published late 2016. In this publication we describe the methods used to evaluate the resultant Stage groupings and the proposals put forward for the 8th edition.

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Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory

Mauro Poggio, Tianyi Hu, Chien-Chun S Pai … (2019)

SUMMARY PD-L1 on the surface of tumor cells binds its receptor PD-1 on effector T cells, thereby suppressing their activity. Antibody blockade of PD-L1 can activate an anti-tumor immune response leading to durable remissions in a subset of cancer patients. Here, we describe an alternative mechanism of PD-L1 activity involving its secretion in tumor-derived exosomes. Removal of exosomal PD-L1 inhibits tumor growth, even in models resistant to anti-PD-L1 antibodies. Exosomal PD-L1 from the tumor suppresses T cell activation in the draining lymph node. Systemically introduced exosomal PD-L1 rescues growth of tumors unable to secrete their own. Exposure to exosomal PD-L1-deficient tumor cells suppresses growth of wild-type tumor cells injected at a distant site, simultaneously or months later. Anti-PD-L1 antibodies work additively, not redundantly, with exosomal PD-L1 blockade to suppress tumor growth. Together, these findings show that exosomal PD-L1 represents an unexplored therapeutic target, which could overcome resistance to current antibody approaches.

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Author and article information

Contributors

Milena Urbini: milena.urbini@irst.emr.it

Paola Ulivi: paola.ulivi@irst.emr.it

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J Exp Clin Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central (London )

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date (Electronic): 22 August 2024

Publication date PMC-release: 22 August 2024

Publication date Collection: 2024

Volume: 43

Electronic Location Identifier: 241

Affiliations

[1 ]GRID grid.419563.c, ISNI 0000 0004 1755 9177, Unit of Biostatistics and Clinical Trials, , IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, ; Meldola, Italy

[2 ]GRID grid.419563.c, ISNI 0000 0004 1755 9177, Biosciences Laboratory, , IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, ; Meldola, Italy

[3 ]Vall d’Hebron Institute of Oncology (VHIO), ( https://ror.org/054xx3904) Barcelona, Spain

[4 ]Thoracic Surgery Department AUSL Romagna, Forlì, Italy

[5 ]Thoracic Surgery Department AUSL Romagna, Ravenna, Italy

[6 ]Thoracic Surgery Department AUSL Romagna, Riccione, Italy

[7 ]GRID grid.412220.7, ISNI 0000 0001 2177 138X, Molecular Laboratory, , University Hospital, Strasbourg University, ; Strasburg, France

[8 ]GRID grid.6292.f, ISNI 0000 0004 1757 1758, Unit of Thoracic Surgery and Lung Transplantation, , IRCCS Azienda Ospedaliero-Universitaria di Bologna, ; Bologna, Italy

[9 ]GRID grid.413866.e, ISNI 0000 0000 8928 6711, Thoracic Surgery Department, , Nouvel Hôpital Civil’, University Hospital, ; Strasburg, France

[10 ]GRID grid.419563.c, ISNI 0000 0004 1755 9177, Oncology Department, , Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori” (IRST) IRCCS, ; Meldola, Italy

Article

Publisher ID: 3156

DOI: 10.1186/s13046-024-03156-y

PMC ID: 11340091

PubMed ID: 39169404

SO-VID: b28ecb0f-6c60-4bf4-925c-d2075667f32a

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 12 April 2024

Date accepted : 8 August 2024

Circulating cell-free and extracellular vesicles-derived microRNA as prognostic biomarkers in patients with early-stage NSCLC: results from RESTING study

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Abstract

Background

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Results

Conclusion

Supplementary Information

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Karger: Oncology

Most cited references 58

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer.

Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory

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