Single-Cell Functional Genomics of Natural Killer Cell Interaction with Blood Cancers

Dufva, Olli; Gandolfi, Sara; Huuhtanen, Jani; Dashevsky, Olga; Saeed, Khalid; Klievink, Jay; Nygren, Petra Johanna; Bouhlal, Jonas; Lahtela, Jenni; Näätänen, Anna; Ghimire, Bishwa; Hannunen, Tiina; Ellonen, Pekka; Duàn, Hanna; Theodoropoulos, Jason; Laajala, Essi; Häkkinen, Aino; Härkönen, Jouni; Pölönen, Petri; Heinäniemi, Merja; Yamano, Shizuka; Shirasaki, Ryosuke; Barbie, David A.; Roth, Jennifer A.; Romee, Rizwan; Sheffer, Michal; Lähdesmäki, Harri; Lee, Dean A.; Simoes, Ricardo de Matos; Kankainen, Matti; Mitsiades, Constantine S.; Mustjoki, Satu

doi:10.1182/blood-2022-167535

Cited by 2 publications

(1 citation statement)

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“…One study showed that suppression of nsGSL synthesis through SPPL3 activity allows for better accessibility of the complement regulator CD59 13 . Another study illustrated that genetic loss of SPPL3 led to a decreased susceptibility of B cell lymphoma cell line NALM6 to NK cell mediated cytotoxicity 14 . These findings were also observed by Zhang and colleagues who, additionally, showed impaired binding of NK cell receptors NKG2D and CD2 to their partners MICA/B and CD58 on cells lacking SPPL3 15 .…”

Section: Introductionmentioning

confidence: 99%

Tumor-expressed SPPL3 supports innate anti-tumor immune responses

Verkerk,

de Waard,

Koomen

et al. 2024

Preprint

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The development of an effective anti-tumor 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 beta1,3-N-acetylglucosaminyltransferase 5 (B3GNT5), in tumor immune escape. We previously demonstrated that loss of signal 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 anti-tumor efficacy of neutrophils, NK cells, and gamma delta 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 gamma delta T cells. Mechanistically, SPPL3 influences trogocytosis and γδ T cell instigated killing through modulation of nsGSL expression while 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.

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Section: Introductionmentioning

confidence: 99%

Tumor-expressed SPPL3 supports innate anti-tumor immune responses

Verkerk,

de Waard,

Koomen

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

Tumor‐Expressed SPPL3 Supports Innate Antitumor Immune Responses

Verkerk,

de Waard,

Koomen

et al. 2024

Eur J Immunol

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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.

show abstract

Single-Cell Functional Genomics of Natural Killer Cell Interaction with Blood Cancers

Cited by 2 publications

References 0 publications

Tumor-expressed SPPL3 supports innate anti-tumor immune responses

Tumor-expressed SPPL3 supports innate anti-tumor immune responses

Tumor‐Expressed SPPL3 Supports Innate Antitumor Immune Responses

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