Sialic Acid-Dependent Inhibition of T Cells by Exosomal Ganglioside GD3 in Ovarian Tumor Microenvironments

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2018 Nov 18

PMID 30446565

Citations 56

Authors

Gautam N Shenoy

Jenni Loyall

Charles S Berenson

Raymond J Kelleher Jr

Vandana Iyer

Sathy V Balu-Iyer

Kunle Odunsi

Richard B Bankert

Affiliations

Soon will be listed here.

Abstract

The tumor microenvironment is rendered immunosuppressive by a variety of cellular and acellular factors that represent potential cancer therapeutic targets. Although exosomes isolated from ovarian tumor ascites fluids have been previously reported to induce a rapid and reversible T cell arrest, the factors present on or within exosomes that contribute to immunosuppression have not been fully defined. In this study, we establish that GD3, a ganglioside expressed on the surface of exosomes isolated from human ovarian tumor ascites fluids, is causally linked to the functional arrest of T cells activated through their TCR. This arrest is inhibited by Ab blockade of exosomal GD3 or by the removal of GD3 exosomes. Empty liposomes expressing GD3 on the surface also inhibit the activation of T cells, establishing that GD3 contributes to the functional arrest of T cells independent of factors present in exosomes. Finally, we demonstrate that the GD3-mediated arrest of the TCR activation is dependent upon sialic acid groups, because their enzymatic removal from exosomes or liposomes results in a loss of inhibitory capacity. Collectively, these data define GD3 as a potential immunotherapeutic target.

Citing Articles

Prominosomes - a particular class of extracellular vesicles containing prominin-1/CD133?.

Karbanova J, Thamm K, Fargeas C, Deniz I, Lorico A, Corbeil D J Nanobiotechnology. 2025; 23(1):61.

PMID: 39881297 PMC: 11776279. DOI: 10.1186/s12951-025-03102-w.

A game of hide-and-seek: how extracellular vesicles evade the immune system.

Ghoshal B, Jhunjhunwala S Drug Deliv Transl Res. 2025; .

PMID: 39843837 DOI: 10.1007/s13346-025-01789-w.

Screening of potential key pathogenic and intervention targets of low-grade glioma based on bioinformatics.

Yi L, Kong W, Jiu Z, Huang Z, Na P, Chen W Transl Cancer Res. 2024; 13(10):5563-5573.

PMID: 39525013 PMC: 11543039. DOI: 10.21037/tcr-24-1662.

Glycan diversity in ovarian cancer: Unraveling the immune interplay and therapeutic prospects.

Wolters-Eisfeld G, Oliveira-Ferrer L Semin Immunopathol. 2024; 46(6):16.

PMID: 39432076 PMC: 11493797. DOI: 10.1007/s00281-024-01025-6.

Measuring carbohydrate recognition profile of lectins on live cells using liquid glycan array (LiGA).

Sojitra M, Schmidt E, Lima G, Carpenter E, McCord K, Atrazhev A Nat Protoc. 2024; .

PMID: 39415074 DOI: 10.1038/s41596-024-01070-3.

References

Thornton M, Kudo D, Rayman P, Horton C, Molto L, Cathcart M . Degradation of NF-kappa B in T cells by gangliosides expressed on renal cell carcinomas. J Immunol. 2004; 172(6):3480-90. DOI: 10.4049/jimmunol.172.6.3480. View

Zhang L, Conejo-Garcia J, Katsaros D, Gimotty P, Massobrio M, Regnani G . Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003; 348(3):203-13. DOI: 10.1056/NEJMoa020177. View

Perdicchio M, Ilarregui J, Verstege M, Cornelissen L, Schetters S, Engels S . Sialic acid-modified antigens impose tolerance via inhibition of T-cell proliferation and de novo induction of regulatory T cells. Proc Natl Acad Sci U S A. 2016; 113(12):3329-34. PMC: 4812702. DOI: 10.1073/pnas.1507706113. View

Bajorin D, Chapman P, Wong G, Coit D, Kunicka J, Dimaggio J . Phase I evaluation of a combination of monoclonal antibody R24 and interleukin 2 in patients with metastatic melanoma. Cancer Res. 1990; 50(23):7490-5. View

Webb T, Li X, Giuntoli 2nd R, Lopez P, Heuser C, Schnaar R . Molecular identification of GD3 as a suppressor of the innate immune response in ovarian cancer. Cancer Res. 2012; 72(15):3744-52. PMC: 3438513. DOI: 10.1158/0008-5472.CAN-11-2695. View

Soiffer R, Chapman P, Murray C, Williams L, Unger P, Collins H . Administration of R24 monoclonal antibody and low-dose interleukin 2 for malignant melanoma. Clin Cancer Res. 1997; 3(1):17-24. View

Lo A, Ma Q, Liu D, Junghans R . Anti-GD3 chimeric sFv-CD28/T-cell receptor zeta designer T cells for treatment of metastatic melanoma and other neuroectodermal tumors. Clin Cancer Res. 2010; 16(10):2769-80. DOI: 10.1158/1078-0432.CCR-10-0043. View

Kelleher Jr R, Balu-Iyer S, Loyall J, Sacca A, Shenoy G, Peng P . Extracellular Vesicles Present in Human Ovarian Tumor Microenvironments Induce a Phosphatidylserine-Dependent Arrest in the T-cell Signaling Cascade. Cancer Immunol Res. 2015; 3(11):1269-78. PMC: 4636911. DOI: 10.1158/2326-6066.CIR-15-0086. View

Landskron J, Helland O, Torgersen K, Aandahl E, Gjertsen B, Bjorge L . Activated regulatory and memory T-cells accumulate in malignant ascites from ovarian carcinoma patients. Cancer Immunol Immunother. 2014; 64(3):337-47. PMC: 11029521. DOI: 10.1007/s00262-014-1636-6. View

10.

Broderick L, Brooks S, Takita H, Baer A, Bernstein J, Bankert R . IL-12 reverses anergy to T cell receptor triggering in human lung tumor-associated memory T cells. Clin Immunol. 2005; 118(2-3):159-69. DOI: 10.1016/j.clim.2005.09.008. View

11.

Berenson C, Nawar H, Kruzel R, Mandell L, Connell T . Ganglioside-binding specificities of E. coli enterotoxin LT-IIc: Importance of long-chain fatty acyl ceramide. Glycobiology. 2012; 23(1):23-31. PMC: 3505011. DOI: 10.1093/glycob/cws123. View

12.

Biswas S, Biswas K, Richmond A, Ko J, Ghosh S, Simmons M . Elevated levels of select gangliosides in T cells from renal cell carcinoma patients is associated with T cell dysfunction. J Immunol. 2009; 183(8):5050-8. PMC: 2890308. DOI: 10.4049/jimmunol.0900259. View

13.

Yun C, Nolan K, Beecham E, Reisfeld R, Junghans R . Targeting of T lymphocytes to melanoma cells through chimeric anti-GD3 immunoglobulin T-cell receptors. Neoplasia. 2001; 2(5):449-59. PMC: 1507984. DOI: 10.1038/sj.neo.7900108. View

14.

Whiteside T . Exosomes and tumor-mediated immune suppression. J Clin Invest. 2016; 126(4):1216-23. PMC: 4811135. DOI: 10.1172/JCI81136. View

15.

Yokota S, Facciponte J, Kelleher Jr R, Shultz L, Loyall J, Parsons R . Changes in ovarian tumor cell number, tumor vasculature, and T cell function monitored in vivo using a novel xenograft model. Cancer Immun. 2013; 13:11. PMC: 3721261. View

16.

Valentino L, Moss T, Olson E, Wang H, Elashoff R, Ladisch S . Shed tumor gangliosides and progression of human neuroblastoma. Blood. 1990; 75(7):1564-7. View

17.

Goyne H, Stone P, Burnett A, Cannon M . Ovarian tumor ascites CD14+ cells suppress dendritic cell-activated CD4+ T-cell responses through IL-10 secretion and indoleamine 2,3-dioxygenase. J Immunother. 2014; 37(3):163-9. PMC: 3954539. DOI: 10.1097/CJI.0000000000000030. View

18.

Berenson C, Nawar H, Yohe H, Castle S, Ashline D, Reinhold V . Mammalian cell ganglioside-binding specificities of E. coli enterotoxins LT-IIb and variant LT-IIb(T13I). Glycobiology. 2009; 20(1):41-54. PMC: 2782182. DOI: 10.1093/glycob/cwp141. View

19.

Merritt W, Taylor B, Reaman G . Coexpression of GD3 ganglioside with CD45RO in resting and activated human T lymphocytes. Cell Immunol. 1996; 173(1):131-48. DOI: 10.1006/cimm.1996.0259. View

20.

Ramakrishna V, Ross M, Petersson M, Gatlin C, Lyons C, Miller C . Naturally occurring peptides associated with HLA-A2 in ovarian cancer cell lines identified by mass spectrometry are targets of HLA-A2-restricted cytotoxic T cells. Int Immunol. 2003; 15(6):751-63. DOI: 10.1093/intimm/dxg074. View