The Role of Sphingolipids in Cancer Immunotherapy

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Jul 2

PMID 34204326

Citations 11

Authors

Paola Giussani

Alessandro Prinetti

Cristina Tringali

Affiliations

Soon will be listed here.

Abstract

Immunotherapy is now considered an innovative and strong strategy to beat metastatic, drug-resistant, or relapsing tumours. It is based on the manipulation of several mechanisms involved in the complex interplay between cancer cells and immune system that culminates in a form of immune-tolerance of tumour cells, favouring their expansion. Current immunotherapies are devoted enforcing the immune response against cancer cells and are represented by approaches employing vaccines, monoclonal antibodies, interleukins, checkpoint inhibitors, and chimeric antigen receptor (CAR)-T cells. Despite the undoubted potency of these treatments in some malignancies, many issues are being investigated to amplify the potential of application and to avoid side effects. In this review, we discuss how sphingolipids are involved in interactions between cancer cells and the immune system and how knowledge in this topic could be employed to enhance the efficacy of different immunotherapy approaches. In particular, we explore the following aspects: how sphingolipids are pivotal components of plasma membranes and could modulate the functionality of surface receptors expressed also by immune cells and thus their functionality; how sphingolipids are related to the release of bioactive mediators, sphingosine 1-phosphate, and ceramide that could significantly affect lymphocyte egress and migration toward the tumour milieu, in addition regulating key pathways needed to activate immune cells; given the renowned capability of altering sphingolipid expression and metabolism shown by cancer cells, how it is possible to employ sphingolipids as antigen targets.

Citing Articles

Sphingosine-1-Phosphate Metabolic Pathway in Cancer: Implications for Therapeutic Targets.

Rufail M, Bassi R, Giussani P Int J Mol Sci. 2025; 26(3).

PMID: 39940821 PMC: 11817292. DOI: 10.3390/ijms26031056.

Anti-ceramide antibody and sphingosine-1-phosphate as potential biomarkers of unresectable non-small cell lung cancer.

Budi L, Hammer D, Varga R, Muller V, Tarnoki A, Tarnoki D Pathol Oncol Res. 2025; 30():1611929.

PMID: 39835329 PMC: 11742942. DOI: 10.3389/pore.2024.1611929.

Sphingolipids in prostate cancer prognosis: integrating single-cell and bulk sequencing.

Zhou S, Sun L, Mao F, Chen J Aging (Albany NY). 2024; 16(9):8031-8043.

PMID: 38713159 PMC: 11131980. DOI: 10.18632/aging.205803.

Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy.

Sukocheva O, Neganova M, Aleksandrova Y, Burcher J, Chugunova E, Fan R Cell Commun Signal. 2024; 22(1):251.

PMID: 38698424 PMC: 11064425. DOI: 10.1186/s12964-024-01626-6.

Sphingosine-1-Phosphate Inhibition Increases Endoplasmic Reticulum Stress to Enhance Oxaliplatin Sensitivity in Pancreatic Cancer.

Gao Z, Janakiraman H, Xiao Y, Kang S, Dong J, Choi J World J Oncol. 2024; 15(2):169-180.

PMID: 38545484 PMC: 10965266. DOI: 10.14740/wjon1768.

References

Federico S, McCarville M, Shulkin B, Sondel P, Hank J, Hutson P . A Pilot Trial of Humanized Anti-GD2 Monoclonal Antibody (hu14.18K322A) with Chemotherapy and Natural Killer Cells in Children with Recurrent/Refractory Neuroblastoma. Clin Cancer Res. 2017; 23(21):6441-6449. PMC: 8725652. DOI: 10.1158/1078-0432.CCR-17-0379. View

Ohnuma K, Uchiyama M, Yamochi T, Nishibashi K, Hosono O, Takahashi N . Caveolin-1 triggers T-cell activation via CD26 in association with CARMA1. J Biol Chem. 2007; 282(13):10117-10131. DOI: 10.1074/jbc.M609157200. View

Nakayama H, Yoshizaki F, Prinetti A, Sonnino S, Mauri L, Takamori K . Lyn-coupled LacCer-enriched lipid rafts are required for CD11b/CD18-mediated neutrophil phagocytosis of nonopsonized microorganisms. J Leukoc Biol. 2007; 83(3):728-41. DOI: 10.1189/jlb.0707478. View

Biswas S, Bryant R, Travis S . Interfering with leukocyte trafficking in Crohn's disease. Best Pract Res Clin Gastroenterol. 2019; 38-39:101617. DOI: 10.1016/j.bpg.2019.05.004. View

Kawamura S, Ohyama C, Watanabe R, Satoh M, Saito S, Hoshi S . Glycolipid composition in bladder tumor: a crucial role of GM3 ganglioside in tumor invasion. Int J Cancer. 2001; 94(3):343-7. DOI: 10.1002/ijc.1482. View

Ruf P, Schafer B, Eissler N, Mocikat R, Hess J, Ploscher M . Ganglioside GD2-specific trifunctional surrogate antibody Surek demonstrates therapeutic activity in a mouse melanoma model. J Transl Med. 2012; 10:219. PMC: 3543252. DOI: 10.1186/1479-5876-10-219. View

Guthmann M, Castro M, Cinat G, Venier C, Koliren L, Bitton R . Cellular and humoral immune response to N-Glycolyl-GM3 elicited by prolonged immunotherapy with an anti-idiotypic vaccine in high-risk and metastatic breast cancer patients. J Immunother. 2006; 29(2):215-23. DOI: 10.1097/01.cji.0000188502.11348.34. View

DAprile C, Prioni S, Mauri L, Prinetti A, Grassi S . Lipid rafts as platforms for sphingosine 1-phosphate metabolism and signalling. Cell Signal. 2021; 80:109929. DOI: 10.1016/j.cellsig.2021.109929. View

Gadiyar V, Lahey K, Calianese D, Devoe C, Mehta D, Bono K . Cell Death in the Tumor Microenvironment: Implications for Cancer Immunotherapy. Cells. 2020; 9(10). PMC: 7599747. DOI: 10.3390/cells9102207. View

10.

Fleurence J, Fougeray S, Bahri M, Cochonneau D, Clemenceau B, Paris F . Targeting -Acetyl-GD2 Ganglioside for Cancer Immunotherapy. J Immunol Res. 2017; 2017:5604891. PMC: 5244029. DOI: 10.1155/2017/5604891. View

11.

Chiricozzi E, Loberto N, Schiumarini D, Samarani M, Mancini G, Tamanini A . Sphingolipids role in the regulation of inflammatory response: From leukocyte biology to bacterial infection. J Leukoc Biol. 2018; 103(3):445-456. DOI: 10.1002/JLB.3MR0717-269R. View

12.

Valentino L, Ladisch S . Circulating tumor gangliosides enhance platelet activation. Blood. 1994; 83(10):2872-7. View

13.

Selvam S, De Palma R, Oaks J, Oleinik N, Peterson Y, Stahelin R . Binding of the sphingolipid S1P to hTERT stabilizes telomerase at the nuclear periphery by allosterically mimicking protein phosphorylation. Sci Signal. 2015; 8(381):ra58. PMC: 4492107. DOI: 10.1126/scisignal.aaa4998. View

14.

Yoon S, Nakayama K, Hikita T, Handa K, Hakomori S . Epidermal growth factor receptor tyrosine kinase is modulated by GM3 interaction with N-linked GlcNAc termini of the receptor. Proc Natl Acad Sci U S A. 2006; 103(50):18987-91. PMC: 1748164. DOI: 10.1073/pnas.0609281103. View

15.

Watanabe R, Ohyama C, Aoki H, Takahashi T, Satoh M, Saito S . Ganglioside G(M3) overexpression induces apoptosis and reduces malignant potential in murine bladder cancer. Cancer Res. 2002; 62(13):3850-4. View

16.

Cavdarli S, Delannoy P, Groux-Degroote S . -acetylated Gangliosides as Targets for Cancer Immunotherapy. Cells. 2020; 9(3). PMC: 7140702. DOI: 10.3390/cells9030741. View

17.

Zhang Y, Springfield R, Chen S, Li X, Feng X, Moshirian R . α-GalCer and iNKT Cell-Based Cancer Immunotherapy: Realizing the Therapeutic Potentials. Front Immunol. 2019; 10:1126. PMC: 6562299. DOI: 10.3389/fimmu.2019.01126. View

18.

Xiao L, Zhou Y, Friis T, Beagley K, Xiao Y . S1P-S1PR1 Signaling: the "Sphinx" in Osteoimmunology. Front Immunol. 2019; 10:1409. PMC: 6603153. DOI: 10.3389/fimmu.2019.01409. View

19.

Furuya H, Shimizu Y, Kawamori T . Sphingolipids in cancer. Cancer Metastasis Rev. 2011; 30(3-4):567-76. DOI: 10.1007/s10555-011-9304-1. View

20.

Okuda T, Shimizu K, Hasaba S, Date M . Induction of specific adaptive immune responses by immunization with newly designed artificial glycosphingolipids. Sci Rep. 2019; 9(1):18803. PMC: 6906409. DOI: 10.1038/s41598-019-55088-9. View