Toll-like Receptors 2, 3, and 4 in Childhood Acute Lymphocytic Leukemia

Authors

  • Matheus Loureiro da Silva Cruz Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre (RS), Brazil. https://orcid.org/0000-0002-1141-0254
  • Rafael Pereira dos Santos Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre (RS), Brazil. https://orcid.org/0000-0003-0949-9648
  • Barbara Kunzler Souza Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre (RS), Brazil. https://orcid.org/0000-0002-1694-1337
  • Mariane da Cunha Jaeger Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre (RS), Brazil. Instituto do Câncer Infantil. Porto Alegre (RS), Brazil. https://orcid.org/0000-0002-3465-4083
  • Camila Alves da Silva Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre (RS), Brazil. https://orcid.org/0000-0002-4243-7767
  • Lauro José Gregianin Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre (RS), Brazil. https://orcid.org/0000-0003-0788-7858
  • Jiseh Fagundes Loss Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre (RS), Brazil. https://orcid.org/0000-0002-0088-514X
  • Rebeca Ferreira Marques Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre (RS), Brazil. https://orcid.org/0000-0001-6447-1029
  • Algemir Lunardi Brunetto Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre (RS), Brazil. Instituto do Câncer Infantil. Porto Alegre (RS), Brazil. https://orcid.org/0000-0003-0668-6894
  • André Tesainer Brunetto Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre (RS), Brazil. Instituto do Câncer Infantil. Porto Alegre (RS), Brazil. https://orcid.org/0000-0002-7958-1279
  • Rafael Roesler Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre (RS), Brazil. https://orcid.org/0000-0001-6016-2261
  • Dra. Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre (RS), Brazil. Instituto do Câncer Infantil. Porto Alegre (RS), Brazil. https://orcid.org/0000-0002-6435-6626

DOI:

https://doi.org/10.32635/2176-9745.RBC.2023v69n3.3676

Keywords:

precursor cell lymphoblastic leukemia-lymphoma, Toll-like receptors

Abstract

Introduction: Acute lymphocytic leukemia (ALL) is the most common cancer type in children and accounts for 80% of pediatric leukemias. Novel targets are necessary to improve survival rates for refractory and relapsed disease. There is accumulating evidence that Toll-like Receptor (TLR) signaling may be associated with outcomes in cancer however little has been described in leukemias. Objective: Analyze the expression and contribution of TLRs to the development of childhood ALL. Method: To evaluate the effect of specific TLR2, TLR3, and TLR4 agonists on the viability and proliferation of childhood ALL cell lines and to analyzed the mRNA expression of these types of TLR in bone marrow blast cells at diagnosis (D0) and induction (D35) in pediatric ALL patients. Results: Treatment with TLR agonists reduced the cell viability of Jurkat and Sup-B15 cell lines. Cell cycle distribution in Jurkat was altered, reducing polyploid cells and increasing sub-G1 phase. Conclusion: It was observed that the cell viability of the cell lines responded with different sensitivities to the agonists. The polyploidy associated with tumor malignancy was reduced, in addition to the increase in the sub-G1 phase indicating an increase in apoptosis. There were differences in TLR expression at D35 between groups at risk of the disease. Patients with high expression of TLR2 and low expression of TLR4 on D35 demonstrated a worse prognosis.

Downloads

Download data is not yet available.

References

Instituto Nacional de Câncer. Estimativa 2023: incidência de câncer no Brasil. Rio de Janeiro: INCA; 2022 [acesso 2023 jul 3]. Disponível em: https://www.inca.gov.br/sites/ufu.sti.inca.local/files//media/document//estimativa-2023.pdf

National Cancer Institute (US) [Internet]. Bethesda (MD): NIH; [2023]. Childhood acute lymphoblastic leukemia treatment (PDQ®) - Health professional version; 2023 Apr 11 [cited 2022 Jun 8]. Available from: https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq

Wells G, Kennedy PT, Dahal LN. Investigating the role of indoleamine 2,3-dioxygenase in acute myeloid leukemia: a systematic review. Front Immunol. 2021;12:651687. doi: https://doi.org/10.3389/fimmu.2021.651687 DOI: https://doi.org/10.3389/fimmu.2021.651687

Rabe JL, Gardner L, Hunter R, et al. IL12 abrogates calcineurin-dependent immune evasion during leukemia progression. Cancer Res. 2019;79(14):3702-13. doi: https://doi.org/10.1158/0008-5472.CAN-18-3800 DOI: https://doi.org/10.1158/0008-5472.CAN-18-3800

Arandi N, Ramzi M, Safaei F, et al. Overexpression of indoleamine 2,3-dioxygenase correlates with regulatory T cell phenotype in acute myeloid leukemia patients with normal karyotype. Blood Res. 2018;53(4):294-8. doi: https://doi.org/10.5045/br.2018.53.4.294 DOI: https://doi.org/10.5045/br.2018.53.4.294

Favere K, Bosman M, Delputte PL, et al. A systematic literature review on the effects of exercise on human Toll-like receptor expression. Exerc Immunol Rev [Internet]. 2021 [cited 2022 Jun 10];27:84-124. Available from: https://img1.wsimg.com/blobby/go/2b32b969-f24b-4b6f-8e61-5d111c218d54/EIR%202021%20Komplett%20KO3.pdf

Sahoo BR. Structure of fish Toll-Like Receptors (TLR) and NOD-like receptors (NLR). Int J Biol Macromol. 2020;161:1602-17. doi: https://doi.org/10.1016/j.ijbiomac.2020.07.293 DOI: https://doi.org/10.1016/j.ijbiomac.2020.07.293

Ayala-Cuellar AP, Cho J, Choi KC. Toll-like receptors: a pathway alluding to cancer control. J Cell Physiol. 2019;234(12):21707-15. doi: https://doi.org/10.1002/jcp.28879 DOI: https://doi.org/10.1002/jcp.28879

Sfanos KS. Targeting Toll-like receptors in cancer prevention. Cancer Prev Res (Phila). 2018;11(5):251-4. doi: https://doi.org/10.1158/1940-6207.CAPR-18-0079 DOI: https://doi.org/10.1158/1940-6207.CAPR-18-0079

Li TT, Ogino S, Qian ZR. Toll-like receptor signaling in colorectal cancer: carcinogenesis to cancer therapy. World J Gastroenterol. 2014;20(47):17699-708. doi: https://doi.org/10.3748/wjg.v20.i47.17699 DOI: https://doi.org/10.3748/wjg.v20.i47.17699

Iacobucci I, Papayannidis C, Lonetti A, et al. Cytogenetic and molecular predictors of outcome in acute lymphocytic leukemia: recent developments. Curr Hemat Malig Rep. 2012;7(2):133-43. doi: https://doi.org/10.1007/s11899-012-0122-5 DOI: https://doi.org/10.1007/s11899-012-0122-5

Chiron D, Bekeredjian-Ding I, Pellat-Deceunynck C, et al. Toll-like receptors: lessons to learn from normal and malignant human B cells. Blood. 2008;112(6):2205-13. doi: https://doi.org/10.1182/blood-2008-02-140673 DOI: https://doi.org/10.1182/blood-2008-02-140673

Conselho Nacional de Saúde (BR). Resolução nº 466, de 12 de dezembro de 2012. Aprova as diretrizes e normas regulamentadoras de pesquisas envolvendo seres humanos. Diário Oficial da União, Brasília, DF. 2013 jun 13; Seção 1:59.

Maino E, Scattolin AM, Viero P, et al. Modern immunotherapy of adult B-lineage acute lymphoblastic leukemia with monoclonal antibodies and chimeric antigen receptor modified t cells. Mediterr J Hematol Infect Dis. 2015;7(1):e2015001. doi: https://doi.org/10.4084/MJHID.2015.001 DOI: https://doi.org/10.4084/mjhid.2015.001

Campesato LF, Silva APM, Cordeiro L, et al. High IL-1R8 expression in breast tumors promotes tumor growth and contributes to impaired antitumor immunity. Oncotarget. 2017;8(30):49470-83. doi: https://doi.org/10.18632/oncotarget.17713 DOI: https://doi.org/10.18632/oncotarget.17713

Zou W. Mechanistic insights into cancer immunity and immunotherapy. Cell Mol Immunol. 2018;15(5):419-20. doi: https://doi.org/10.1038/s41423-018-0011-5 DOI: https://doi.org/10.1038/s41423-018-0011-5

Chen Z, Wang JH. How the signaling crosstalk of B Cell Receptor (BCR) and Co-receptors regulates antibody class switch recombination: a new perspective of checkpoints of BCR signaling. Front Immunol. 2021;12:663443. doi: https://doi.org/10.3389/fimmu.2021.663443 DOI: https://doi.org/10.3389/fimmu.2021.663443

Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11(5):373-84. doi: https://doi.org/10.1038/ni.1863 DOI: https://doi.org/10.1038/ni.1863

Sivori S, Pende D, Quatrini L, et al. NK cells and ILCs in tumor immunotherapy. Mol Aspects Med. 2021;80:100870. doi: https://doi.org/10.1016/j.mam.2020.100870 DOI: https://doi.org/10.1016/j.mam.2020.100870

Collinson-Pautz MR, Chang WC, Lu A, et al. Constitutively active MyD88/CD40 costimulation enhances expansion and efficacy of chimeric antigen receptor T cells targeting hematological malignancies. Leuk. 2019;33:2195-2207. doi: https://doi.org/10.1038/s41375-019-0417-9 DOI: https://doi.org/10.1038/s41375-019-0417-9

Szymańska A, Bojarska-Junak A, Drobiecki A, et al. TLR2 expression on leukemic B cells from patients with chronic lymphocytic leukemia. Arch Immunol Ther Exp (Warsz). 2019;67(1):55-65. doi: https://doi.org/10.1007/s00005-018-0523-9 DOI: https://doi.org/10.1007/s00005-018-0523-9

Collins PE, Somma D, Kerrigan D, et al. The IκB-protein BCL-3 controls Toll-like receptor-induced MAPK activity by promoting TPL-2 degradation in the nucleus. Proc Natl Acad Sci USA. 2019;116(51):25828-38. doi: https://doi.org/10.1073/pnas.1900408116 DOI: https://doi.org/10.1073/pnas.1900408116

Spaner DE, Venema R, Huang J, et al. Association of blood IgG with tumor necrosis factor-alpha and clinical course of chronic lymphocytic leukemia. EBioMedicine. 2018;35:222-32. doi: https://doi.org/10.1016/j.ebiom.2018.08.045 DOI: https://doi.org/10.1016/j.ebiom.2018.08.045

Luo X, Zhang X, Gan L, et al. The outer membrane protein Tp92 of Treponema pallidum induces human mononuclear cell death and IL-8 secretion. J Cell Mol Med. 2018;22(12):6039-54. doi: https://doi.org/10.1111/jcmm.13879 DOI: https://doi.org/10.1111/jcmm.13879

Khajeh Alizadeh Attar M, Anwar MA, Eskian M, et al. Basic understanding and therapeutic approaches to target toll-like receptors in cancerous microenvironment and metastasis. Med Res Rev. 2018;38(5):1469-84. doi: https://doi.org/10.1002/med.21480 DOI: https://doi.org/10.1002/med.21480

Meliț LE, Mărginean CO, Mărginean CD, et al. The relationship between Toll-like receptors and Helicobacter pylori-related gastropathies: still a controversial topic. J Immunol Res. 2019;2019:8197048. doi: https://doi.org/10.1155/2019/8197048 DOI: https://doi.org/10.1155/2019/8197048

Spanou E, Kalisperati P, Pateras IS, et al. Genetic Variability as a regulator of TLR4 and NOD signaling in response to bacterial driven DNA Damage Response (DDR) and inflammation: focus on the gastrointestinal (GI) tract. Front Genet. 2017;8:65. doi: https://doi.org/10.3389/fgene.2017.00065 DOI: https://doi.org/10.3389/fgene.2017.00065

Paarnio K, Väyrynen S, Klintrup K, et al. Divergent expression of bacterial wall sensing Toll-like receptors 2 and 4 in colorectal cancer. World J Gastroenterol. 2017;23(26):4831-8. doi: https://doi.org/10.3748/wjg.v23.i26.4831 DOI: https://doi.org/10.3748/wjg.v23.i26.4831

Rybka J, Butrym A, Wróbel T, et al. The expression of Toll-like receptors in patients with B-cell chronic lymphocytic leukemia. Arch Immunol Ther Exp (Warsz). 2016;64(Suppl 1):147-50. doi: https://doi.org/10.1007/s00005-016-0433-7 DOI: https://doi.org/10.1007/s00005-016-0433-7

Rybka J, Butrym A, Wróbel T, et al. The expression of Toll-like receptors in patients with acute myeloid leukemia treated with induction chemotherapy. Leuk Res. 2015;39(3):318-22. doi: https://doi.org/10.1016/j.leukres.2015.01.002 DOI: https://doi.org/10.1016/j.leukres.2015.01.002

Sánchez-Cuaxospa M, Contreras-Ramos A, Pérez-Figueroa E, et al. Low expression of Toll-like receptors in peripheral blood mononuclear cells of pediatric patients with acute lymphoblastic leukemia. Int J Oncol. 2016;49(2):675-81. doi: https://doi.org/10.3892/ijo.2016.3569 DOI: https://doi.org/10.3892/ijo.2016.3569

Maharjan S, Park BK, Lee SI, et al. Gomisin G suppresses the growth of colon cancer cells by attenuation of AKT phosphorylation and arrest of cell cycle progression. Biomol Ther (Seoul). 2019;27(2):210-5. doi: https://doi.org/10.4062/biomolther.2018.054 DOI: https://doi.org/10.4062/biomolther.2018.054

Alonso-Lecue P, Pedro I, Coulon V, et al. Inefficient differentiation response to cell cycle stress leads to genomic instability and malignant progression of squamous carcinoma cells. Cell Death Dis. 2017;8:e2901. doi: https://doi.org/10.1038/cddis.2017.259 DOI: https://doi.org/10.1038/cddis.2017.259

Jo Y, Shin DY. Repression of the F-box protein Skp2 is essential for actin damage-induced tetraploid G1 arrest. BMB Rep. 2017;50(7):379-83. doi: https://doi.org/10.5483/bmbrep.2017.50.7.063 DOI: https://doi.org/10.5483/BMBRep.2017.50.7.063

Wang D, Xiao PL, Duan HX, et al. Peptidoglycans promotes human leukemic THP-1 cell apoptosis and differentiation. Asian Pac J Cancer Prev. 2012;13(12):6409-13. doi: https://doi.org/10.7314/apjcp.2012.13.12.6409 DOI: https://doi.org/10.7314/APJCP.2012.13.12.6409

Salaun B, Zitvogel L, Asselin-Paturel C, et al. TLR3 as a biomarker for the therapeutic efficacy of double-stranded RNA in breast cancer. Cancer Res. 2011;71(5):1607-14. doi: https://doi.org/10.1158/0008-5472.CAN-10-3490 DOI: https://doi.org/10.1158/0008-5472.CAN-10-3490

Li H, Gao C, Liu C, et al. A review of the biological activity and pharmacology of cryptotanshinone, an important active constituent in Danshen. Biomed Pharmacother. 2021;137:111332. doi: https://doi.org/10.1016/j.biopha.2021.111332 DOI: https://doi.org/10.1016/j.biopha.2021.111332

Gliozzi M, Scicchitano M, Bosco F, et al. Modulation of nitric oxide synthases by oxidized ldls: role in vascular inflammation and atherosclerosis development. Int J Mol Sci. 2019;20(13):3294. doi: https://doi.org/10.3390/ijms20133294 DOI: https://doi.org/10.3390/ijms20133294

Downloads

Published

2023-07-06

How to Cite

1.
Cruz ML da S, Santos RP dos, Souza BK, Jaeger M da C, Silva CA da, Gregianin LJ, Loss JF, Marques RF, Brunetto AL, Brunetto AT, Roesler R, Farias CB de. Toll-like Receptors 2, 3, and 4 in Childhood Acute Lymphocytic Leukemia. Rev. Bras. Cancerol. [Internet]. 2023 Jul. 6 [cited 2024 May 14];69(3):e-053676. Available from: https://rbc.inca.gov.br/index.php/revista/article/view/3676

Issue

Vol. 69 No. 3 (2023): July/Aug./Sept.

Section

ORIGINAL ARTICLE

License

Os direitos morais e intelectuais dos artigos pertencem aos respectivos autores, que concedem à RBC o direito de publicação.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Most read articles by the same author(s)