Related Experiment Video
Updated: Jun 5, 2025
Using Human Induced Pluripotent Stem Cells for the Generation of Tumor Antigen-specific T Cells
Published on: October 24, 2019
Tumor-Expressed SPPL3 Supports Innate Antitumor Immune Responses
Tamara Verkerk1,2, Antonius A de Waard1,2, Sofie J I Koomen1,2
1Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands.
Abstract:
The development of an effective antitumor response relies on the synergistic actions of various immune cells that recognize tumor cells via distinct receptors. Tumors, however, often manipulate receptor-ligand interactions to evade recognition by the immune system. Recently, we highlighted the role of neolacto-series glycosphingolipids (nsGSLs), produced by the enzyme β1,3-N-acetylglucosaminyltransferase 5 (B3GNT5), in tumor immune escape. We previously demonstrated that loss of signal peptide peptidase like 3 (SPPL3), an inhibitor of B3GNT5, results in elevated levels of nsGSLs and impairs CD8 T cell activation. The impact of loss of SPPL3 and an elevated nsGSL profile in tumor cells on innate immune recognition remains to be elucidated. This study investigates the antitumor efficacy of neutrophils, NK cells, and γδ T cells on tumor cells lacking SPPL3. Our findings demonstrate that SPPL3-deficient target cells are less susceptible to trogocytosis by neutrophils and killing by NK cells and γδ T cells. Mechanistically, SPPL3 influences trogocytosis and γδ T cell-instigated killing through modulation of nsGSL expression, whereas SPPL3-mediated reduced killing by NK cells is nsGSL-independent. The nsGSL-dependent SPPL3 sensitivity depends on the proximity of surface receptor domains to the cell membrane and the affinity of receptor-ligand interactions as shown with various sets of defined antibodies. Thus, SPPL3 expression by tumor cells alters crosstalk with immune cells through the receptor-ligand interactome thereby driving escape not only from adaptive but also from innate immunity. These data underline the importance of investigating a potential synergism of GSL synthesis inhibitors with current immune cell-activating immunotherapies.
Insights
Tumor cells lacking signal peptide peptidase like 3 (SPPL3) evade immune cells by altering glycosphingolipid (GSL) expression. This study shows SPPL3 deficiency impairs innate immune cell recognition and killing of tumor cells.
Area of Science:
- Immunology
- Cancer Biology
- Glycobiology
Background:
- Effective antitumor responses depend on immune cells recognizing tumor cells via specific receptors.
- Tumors can evade immune detection by manipulating receptor-ligand interactions.
- Neolacto-series glycosphingolipids (nsGSLs) are implicated in tumor immune escape, with their production regulated by β1,3-N-acetylglucosaminyltransferase 5 (B3GNT5).
Purpose of the Study:
- To investigate the impact of signal peptide peptidase like 3 (SPPL3) deficiency and elevated nsGSLs in tumor cells on innate immune recognition.
- To determine the antitumor efficacy of neutrophils, natural killer (NK) cells, and γδ T cells against SPPL3-deficient tumor cells.
Main Methods:
- Assessing the susceptibility of SPPL3-deficient tumor cells to trogocytosis by neutrophils and killing by NK cells and γδ T cells.
- Investigating the mechanistic role of SPPL3 and nsGSL expression in immune cell interactions.
- Analyzing the influence of receptor proximity and ligand affinity on SPPL3-mediated immune evasion using antibodies.
Main Results:
- SPPL3-deficient tumor cells exhibited reduced susceptibility to trogocytosis by neutrophils and killing by γδ T cells, mediated by nsGSL modulation.
- SPPL3 deficiency also reduced NK cell-mediated killing, but this effect was independent of nsGSL levels.
- SPPL3 expression in tumor cells alters immune cell crosstalk via the receptor-ligand interactome, promoting escape from both adaptive and innate immunity.
Conclusions:
- SPPL3 plays a critical role in tumor immune escape by modulating glycosphingolipid expression and influencing interactions with innate immune cells.
- Targeting SPPL3 or GSL synthesis may enhance the efficacy of immunotherapies that rely on immune cell activation.
- Further research into combining GSL synthesis inhibitors with immune cell-activating therapies is warranted.
Related Concept Videos
01:27Tumor Immunotherapy
02:23Abnormal Proliferation
02:17The Tumor Microenvironment