Ganglioside Inhibition of CD8+ T Cell Cytotoxicity: Interference with Lytic Granule Trafficking and Exocytosis

Abstract

Granule exocytosis-mediated cytotoxicity by CD8+ CTL plays a crucial role in adaptive immunity to tumors and to intracellular pathogens. This T cell effector function has been shown to be defective in various murine tumor models and in human cancer. However, factors and their mechanisms that cause inhibition of CD8+ T cell lytic function in tumor-bearing hosts remain to be fully defined. We postulate that gangliosides, highly expressed on tumor cell membranes, actively shed into the tumor microenvironment, and having well-established immunosuppressive properties, may be such a factor. We exposed primary mouse CD8+ CTL to gangliosides derived from three sources (tumors and normal brain). This significantly inhibited cytotoxicity-mediated by granule exocytosis, that is, cytotoxicity of alloantigen-specific and polyclonal CD8+ CTL in vitro. These molecules did not interfere with the interaction of CD8+ T cells with their cognate targets. Rather, they inhibited lytic granule release in response both to TCR engagement and to stimuli that induce granule release in a nonpolarized manner. At the subcellular level, confocal microscopic imaging identified inhibition of polarization of lytic granules to the immunological synapse upon target cell recognition. Thus, tumor-shed gangliosides suppress lytic activity of CD8+ T cells by a novel mechanism, that is, inhibition of trafficking of lytic granules in response to TCR engagement, as well as by interfering with the process of granule exocytosis in CD8+ T cells.

Reprogramming the tumor microenvironment: tumor-induced immunosuppressive factors paralyze T cells

“…105,107 Furthermore, soluble gangliosides have been shown to disrupt nuclear factor kappa B (NF-B) function in immune cells 108,109 as well as lytic granule trafficking and exocytosis in CD8 C T cells. 110 Thus, gangliosides that are shed into the microenvironment can disrupt the normal functioning of T cells in numerous ways. Therapies targeting the tumor gangliosides GD2, GM3, and GD3 may potentially prevent gangliosides from inducing T-cell dysfunction.…”

Gangliosides Drive the Tumor Infiltration and Function of Myeloid-Derived Suppressor Cells

“…This novel immunoregulatory mechanism of tumor gangliosides—inhibition through enhancement of MDSC number and their function in tumors—is complemented by direct inhibitory effects of gangliosides on cytotoxic T cell function (29), suggesting a highly effective immunosuppressive process that tumors may use early on to implant and establish themselves, and a process that links rapid ganglioside metabolism to enhanced tumor growth. The deficit of infiltrating MDSC in ganglioside-poor DKO tumors may also in part explain the negative impact that the absence of gangliosides has on another process important to tumor growth, angiogenesis (30).…”

Targeting of tumor-associated gangliosides with antibodies affects signaling pathways and leads to cell death including apoptosis

“…Tumor-associated gangliosides are also shed to microenvironment and detected in sera of cancer patients. There, they can affect functions of immune cells, e.g., inhibit CTL cytotoxicity and on the contrary attract myeloid derived suppressor cells [30,31]. Finally, in 2014, Liu et al showed that gangliosides enhance tumor angiogenesis, by comparing tumor vasculature generated in mice by wild type and GM3 synthase/GM2 synthase deficient embryonic fibroblasts that were stably transfected with c-myc and H-Ras.…”