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Characterization of purinergic signaling in tumor-infiltrating lymphocytes from lower- and high-grade gliomas

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Abstract

Malignant gliomas are highly heterogeneous glia-derived tumors that present an aggressive and invasive nature, with a dismal prognosis. The multi-dimensional interactions between glioma cells and other tumor microenvironment (TME) non-tumoral components constitute a challenge to finding successful treatment strategies. Several molecules, such as extracellular purines, participate in signaling events and support the immunosuppressive TME of glioma patients. The purinergic signaling and the ectoenzymes network involved in the metabolism of these extracellular nucleotides are still unexplored in the glioma TME, especially in lower-grade gliomas (LGG). Also, differences between IDH-mutant (IDH-Mut) versus wild-type (IDH-WT) gliomas are still unknown in this context. For the first time, to our knowledge, this study characterizes the TME of LGG, high-grade gliomas (HGG) IDH-Mut, and HGG IDH-WT patients regarding purinergic ectoenzymes and P1 receptors, focusing on tumor-infiltrating lymphocytes. Here, we show that ectoenzymes from both canonical and non-canonical pathways are increased in the TME when compared to the peripheral blood. We hypothesize this enhancement supports extracellular adenosine generation, hence increasing TME immunosuppression.

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All data generated or analysed during this study are included in this published article [and its supplementary information files].

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Acknowledgements

The authors would like to thank all the patients who have agreed to participate in this study and their families. We also thank all from Departamento de Neurocirurgia team (Hospital Cristo Redentor) for their work and collaboration, and all our collaborators for the technical support provided. Finally, we thank the funding agencies Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) and Instituto Nacional de Ciência e Tecnologia (INCT).

Funding

This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; n° 406035/2021–0 and PQ n° 311580/2021–1, Figueiró F), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS/PQG grant no. 21/2551–0001972-7) and Instituto Nacional de Ciência e Tecnologia—INCT/CNPq/CAPES/FAPERGS grant no. 465671/2014–4.). This study was financed in part by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; 140977/2019–8).

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Authors and Affiliations

  1. Programa de Pós-Graduação Em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, RS, Brazil

    Juliete Nathali Scholl, Augusto Ferreira Weber, Camila Kehl Dias, Vinícius Pierdoná Lima, Ana Maria Oliveira Battastini & Fabrício Figueiró

  2. Programa de Pós-Graduação Em Pediatria E Saúde da Criança, Escola de Medicina, PUCRS, Porto Alegre, RS, Brazil

    Lucas Kich Grun

  3. Departamento de Neurocirurgia, Hospital Cristo Redentor, Porto Alegre, Brazil

    Diego Zambonin, Eduardo Anzolin, Wanderson Willian Dos Santos Dias, Willian Pegoraro Kus & Paulo Valdeci Worm

  4. Programa de Pós-Graduação Em Biologia Celular E Molecular, Escola de Ciências da Saúde E da Vida, PUCRS, Porto Alegre, RS, Brazil

    Florencia Barbé-Tuana

  5. Departmento de Cirurgia, Universidade Federal de Ciências da Saúde de Porto Alegre, Rio Grande Do Sul, Porto Alegre, Brazil

    Paulo Valdeci Worm

  6. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, RS, Brazil

    Fabrício Figueiró

Authors
  1. Juliete Nathali Scholl
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  2. Augusto Ferreira Weber
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  3. Camila Kehl Dias
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  4. Vinícius Pierdoná Lima
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  5. Lucas Kich Grun
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  6. Diego Zambonin
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  7. Eduardo Anzolin
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  8. Wanderson Willian Dos Santos Dias
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  9. Willian Pegoraro Kus
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  10. Florencia Barbé-Tuana
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  11. Ana Maria Oliveira Battastini
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  13. Fabrício Figueiró
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Contributions

Conceptualization: Juliete Nathali Scholl, Fabrício Figueiró; Methodology: Juliete Nathali Scholl, Augusto Ferreira Weber, Camila Kehl Dias, Vinícius Pierdoná Lima, Lucas Kich Grun, Diego Zambonin, Eduardo Anzolin, Wanderson Willian Dos Santos Dias, Willian Pegoraro Kus; Validation: Juliete Nathali Scholl, Augusto Ferreira Weber, Camila Kehl Dias, Vinícius Pierdoná Lima; Formal analysis and Investigation: Juliete Nathali Scholl, Augusto Ferreira Weber, Camila Kehl Dias, Vinícius Pierdoná Lima Writing—original draft: Juliete Nathali Scholl; Writing—review & editing: Juliete Nathali Scholl, Augusto Ferreira Weber, Camila Kehl Dias, Vinícius Pierdoná Lima, Lucas Kich Grun, Diego Zambonin, Eduardo Anzolin, Wanderson Willian Dos Santos Dias, Willian Pegoraro Kus, Florencia Barbé-Tuana, Ana Maria Oliveira Battastini, Paulo Valdeci Worm, Fabrício Figueiró; Visualization: Juliete Nathali Scholl; Supervision: Fabrício Figueiró; Project administration: Juliete Nathali Scholl, Fabrício Figueiró; Funding acquisition: Juliete Nathali Scholl, Fabrício Figueiró.

Corresponding author

Correspondence to Fabrício Figueiró.

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Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Conflicts of interest

Juliete Nathali Scholl declares that she has no conflict of interest.

Augusto Ferreira Weber declares that he has no conflict of interest.

Camila Kehl Dias declares that she has no conflict of interest.

Vinícius Pierdoná Lima declares that he has no conflict of interest.

Lucas Kich Grun declares that he has no conflict of interest.

Diego Zambonin declares that he has no conflict of interest.

Eduardo Anzolin declares that he has no conflict of interest.

Wanderson Willian Dos Santos Dias declares that he has no conflict of interest.

Willian Pegoraro Kus declares that he has no conflict of interest.

Florencia Barbé-Tuana declares that she has no conflict of interest.

Ana Maria Oliveira Battastini declares that she has no conflict of interest.

Paulo Valdeci Worm declares that he has no conflict of interest.

Fabrício Figueiró declares that he has no conflict of interest.

Ethics approval

The study was conducted in accordance with the 1964 Helsinki Declaration, and the protocol was approved by the Ethics Committee of the Grupo Hospitalar Conceição and the Universidade Federal do Rio Grande do Sul (Project n°: 4.343.931, CAAE n°: 24997119.8.3002.5530; and Project number: 3.986.203, CAAE number: 24997119.8.0000.5347).

Consent to participate

Informed consent was obtained from all individual participants included in the study.

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Supplementary Information

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Supplementary Fig. 1

Plasmatic purine levels. Nucleotides (A - C) and nucleosides (D - G) levels in LGG, HGG IDH-Mut, and HGG IDH-WT patient plasma samples were evaluated by HPLC. Data represent a combination of experiments involving individual patients and are displayed as the mean ± SD (PNG 55 kb)

High Resolution Image (TIFF 720 KB)

Supplementary Fig. 2

Kaplan-Meier analysis showing the influence of CD38 (A, D, G, J, M, and P), ENTPD1 (B, E, H, K, N, Q, S, and U), and NT5E (C, F, I, L, O, R, T, and V) gene expression of HGG and LGG in patients with high Treg, CD8+, CD19+, and NK cell gene signature (PNG 453 kb)

High Resolution Image (TIFF 6889 KB)

Supplementary file3 (DOCX 24 KB)

Supplementary file4 (DOCX 17 KB)

Supplementary file5 (DOCX 16 KB)

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Scholl, J.N., Weber, A.F., Dias, C.K. et al. Characterization of purinergic signaling in tumor-infiltrating lymphocytes from lower- and high-grade gliomas. Purinergic Signalling 20, 47–64 (2024). https://doi.org/10.1007/s11302-023-09931-4

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