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Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) as an undetermined tool in tumor cells

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Abstract

In the tumor microenvironment, the function of T cells is a fate-changer for tumor progression. In the meantime, CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are vital role players in the controlling activity of T cells as an activator and deactivator, respectively. In T cells in comparison to CD28, the molecular mechanism of CTLA-4 is unclear. In addition, despite the fact that most tumor cell types express CTLA-4, its role in tumor cells is not well understood and only few studies focused on the role of CTLA-4 signaling in tumor cells. It is illustrated that CTLA-4 signaling causes PD-L1 expression in tumor cells. However, numerous characteristics of CTLA-4 signaling in tumor cells are ambiguous and require to be described. In this article, we proposed that the CTLA-4 signaling during immunotherapy with anti-CTLA-4 antibodies may cause poor responses by patients. In addition, we attract attention to several fundamental questions regarding CTLA-4 signaling in tumor cells. Overall, the CTLA-4 signaling function and the related gaps about its role in tumor cells in the present review are challenged.

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Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Abbreviations

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

APC:

Antigen-presenting cells

TCR:

T-cell receptor

DC:

Dendritic cell

NK cell:

Natural killer cell

sCTLA-4:

Soluble CTLA-4

RAS:

Rat sarcoma virus

PI3K:

Phosphatidylinositol 3-kinase

PKC-Ɵ:

Protein kinase C Ɵ

PLCɣ:

Phospholipase Cɣ

SHP2:

Src homology 2-containing tyrosine phosphatase 2

PP2A:

Serine–threonine phosphatase protein phosphatase 2A

ZAP70:

Zeta-chain-associated protein kinase 70

AKT:

A serine/threonine protein kinase

GLU1:

Glucose transporter 1

SNAT:

Sodium‐coupled neutral amino acid transporter 1

NIH:

National Institutes of Health

PD-L1:

Programmed death ligand-1

EGFR:

Epidermal growth factor receptor

MEK:

Mitogen-activated protein kinase

ERK:

Extracellular signal-regulated kinase

NA:

Not available

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Acknowledgements

The authors would like to appreciate BioRender.com for its services. Figures 1 and 2 were created with Biorender.com.

Funding

This work received no specific grant from any funding agency. The author thanks the National Council for the Improvement of Higher Education (CAPES) and the National Council for Scientific and Technological Development (CNPq) for the support of the scholarship.

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Author notes

  1. The authors Parviz Azimnasab-sorkhabi and Maryam Soltani-asl have contributed equally to this work (co-first authors).

Authors and Affiliations

  1. Department of Surgery, School of Veterinary Medicine and Animal Sciences, University of Sao Paulo, Sao Paulo, Brazil

    Parviz Azimnasab-sorkhabi, Maryam Soltani-asl & Jose´ Roberto Kfoury Junior

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  1. Parviz Azimnasab-sorkhabi
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Contributions

All authors contributed to the study’s conception and design. The original idea for the article was designed by PA, MS, and JRKJ. Literature searches and preparing the first draft of the manuscript were performed by PA and MS. Critically revising was performed by PA, MS, and JRKJ. All authors read and approved the final manuscript.

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Correspondence to Parviz Azimnasab-sorkhabi.

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Azimnasab-sorkhabi, P., Soltani-asl, M. & Kfoury Junior, J.R. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) as an undetermined tool in tumor cells. Human Cell 36, 1225–1232 (2023). https://doi.org/10.1007/s13577-023-00893-8

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