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. 2023 Oct 3:14:1270981.
doi: 10.3389/fimmu.2023.1270981. eCollection 2023.

The entanglement of extracellular matrix molecules and immune checkpoint inhibitors in cancer: a systematic review of the literature

Albina Fejza  1 , Greta Carobolante  2 , Evelina Poletto  2 , Lucrezia Camicia  2 , Giorgia Schinello  2 , Emanuele Di Siena  2 , Giuseppe Ricci  3   4 , Maurizio Mongiat  2 , Eva Andreuzzi  3
Affiliations

The entanglement of extracellular matrix molecules and immune checkpoint inhibitors in cancer: a systematic review of the literature

Albina Fejza et al. Front Immunol. .

Abstract

Introduction: Immune-checkpoint inhibitors (ICIs) have emerged as a core pillar of cancer therapy as single agents or in combination regimens both in adults and children. Unfortunately, ICIs provide a long-lasting therapeutic effect in only one third of the patients. Thus, the search for predictive biomarkers of responsiveness to ICIs remains an urgent clinical need. The efficacy of ICIs treatments is strongly affected not only by the specific characteristics of cancer cells and the levels of immune checkpoint ligands, but also by other components of the tumor microenvironment, among which the extracellular matrix (ECM) is emerging as key player. With the aim to comprehensively describe the relation between ECM and ICIs' efficacy in cancer patients, the present review systematically evaluated the current literature regarding ECM remodeling in association with immunotherapeutic approaches.

Methods: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and was registered at the International Prospective Register of Systematic Reviews (PROSPERO, CRD42022351180). PubMed, Web of Science, and Scopus databases were comprehensively searched from inception to January 2023. Titles, abstracts and full text screening was performed to exclude non eligible articles. The risk of bias was assessed using the QUADAS-2 tool.

Results: After employing relevant MeSH and key terms, we identified a total of 5070 studies. Among them, 2540 duplicates, 1521 reviews or commentaries were found and excluded. Following title and abstract screening, the full text was analyzed, and 47 studies meeting the eligibility criteria were retained. The studies included in this systematic review comprehensively recapitulate the latest observations associating changes of the ECM composition following remodeling with the traits of the tumor immune cell infiltration. The present study provides for the first time a broad view of the tight association between ECM molecules and ICIs efficacy in different tumor types, highlighting the importance of ECM-derived proteolytic products as promising liquid biopsy-based biomarkers to predict the efficacy of ICIs.

Conclusion: ECM remodeling has an important impact on the immune traits of different tumor types. Increasing evidence pinpoint at ECM-derived molecules as putative biomarkers to identify the patients that would most likely benefit from ICIs treatments.

Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022351180, identifier CRD42022351180.

Keywords: breast cancer; cancer; extracellular matrix; gastrointestinal cancer; gynecological cancer; immune checkpoint inhibitors; melanoma; pediatric cancer.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
PRISMA flow diagram of the studies’ screening and selection.
Figure 2
Figure 2
Risk of bias summary of the included papers, based on QUADAS-2 tool. NA, not applicable.
Figure 3
Figure 3
Schematic representation of the suitable approaches aimed at evaluating ECM remodeling as a tool to predict the efficacy of ICIs and to help the clinical decision-making process. Created with BioRender.com.
See this image and copyright information in PMC

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References

    1. Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discovery (2018) 8(9):1069–86. doi: 10.1158/2159-8290.CD-18-0367 - DOI - PubMed
    1. Johnson DB, Nebhan CA, Moslehi JJ, Balko JM. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat Rev Clin Oncol (2022) 19(4):254–67. doi: 10.1038/s41571-022-00600-w - DOI - PMC - PubMed
    1. Lu Y, Wang W, Wang F. Clinical benefits of PD-1 inhibitors in specific subgroups of patients with advanced esophageal squamous cell carcinoma: a systematic review and meta-analysis of phase 3 randomized clinical trials. Front Immunol (2023) 14:14. doi: 10.3389/fimmu.2023.1171671 - DOI - PMC - PubMed
    1. Iranzo P, Callejo A, Assaf JD, Molina G, Lopez DE, Garcia-Illescas D, et al. . Overview of checkpoint inhibitors mechanism of action: role of immune-related adverse events and their treatment on progression of underlying cancer. Front Med (2022) 9:875974. doi: 10.3389/fmed.2022.875974 - DOI - PMC - PubMed
    1. Wang J, Yang T, Xu J. Therapeutic development of immune checkpoint inhibitors. Adv Exp Med Biol (2020) 1248:619–49. doi: 10.1007/978-981-15-3266-5_23 - DOI - PubMed

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