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

Abstract

The tumor microenvironment is rendered immunosuppressive by a variety of cellular and acellular factors, which represent potential cancer therapeutic targets. While 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. Here, 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 T cell receptor. This arrest is inhibited by antibody 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, since their enzymatic removal from exosomes or liposomes results in a loss of inhibitory capacity. Collectively, these data define GD3 as a potential immunotherapeutic target.

When Little Things Make a Big Difference

“…The authors identify exosomes as an immune checkpoint that arrests T cell function, thus possibly contributing to the pathology of these chronic inflammatory diseases. This study also demonstrates that targeting immunosuppressive lipids expressed on the surface of these exosomes may represent a viable strategy to reverse their effects, akin to similar findings in tumor microenvironments (Kelleher et al 2015;Shenoy et al 2018). This brings us to the next article, which also describes the immunosuppressive role of exosomes, but in the context of tumors.…”

Exosomes promote pre-metastatic niche formation in ovarian cancer

“…Exosomes isolated from the ascites of ovarian cancer can induce a rapid and reversible T cell arrest [17]. One recent study found GD3, a ganglioside expressed on the surface of exosomes isolated from ascites, to arrest T cells via acting on their T-cell receptor (TCR) [46]. Ovarian cancer associated exosomes can also induce the production of IL-6 within monocytes through toll-like receptor (TLR) activation.…”

Exosomes as mediators of immune regulation and immunotherapy in cancer

“…Exosomal PD-L1 suppressed T cell functions and had predictive value in the response of melanoma patients to targeted and ICB therapies [22] Plasma of gastric cancer patients PD-L1 T cells 5-FU enhanced the levels of circulating exosomal PD-L1 in gastric cancer patients. In vitro, exosomal PD-L1 induced apoptosis of Jurkat cells and reduced activation of PBMCs [58] NPC patient plasma of NPC-bearing mice Galectin-9 CD4 + T cells Exosomal Galectin-9 induced apoptosis of EBV-specific CD4 + T cells upon binding to Tim-3 [59] NPC patient-derived serum and NPC cells miRNAs T cells Exosomes inhibited T cell proliferation, induced a T reg phenotype, and impaired T H 1 and T H 17 differentiation [60] HCC cells 14-3-3f T cells Exosomal 14-3-3f engaged an immunosuppressive phenotype in recipient T cells [61] Ascites from ovarian cancer patients Ganglioside GD3 T cells Exosomal GD3 decreased T cell activation [62] Ascites from ovarian cancer patients -T cells Exosomes from ascites suppressed T cell functions [63] Plasma of melanoma patients -CD8 + T cells and NK cells…”