Molecular Basis and Role of Siglec-7 Ligand Expression on Chronic Lymphocytic Leukemia B Cells

Abstract

Siglec-7 (sialic acid–binding immunoglobulin-like lectin 7) is an immune checkpoint-like glycan recognition protein on natural killer (NK) cells. Cancer cells often upregulate Siglec ligands to subvert immunosurveillance, but the molecular basis of Siglec ligands has been elusive. In this study, we investigated Siglec-7 ligands on chronic lymphocytic leukemia (CLL) B cells. CLL B cells express higher levels of Siglec-7 ligands compared with healthy donor B cells, and enzymatic removal of sialic acids or sialomucins makes them more sensitive to NK cell cytotoxicity. Gene knockout experiments have revealed that the sialyltransferase ST6GalNAc-IV is responsible for the biosynthesis of disialyl-T (Neu5Acα2–3Galβ1–3[Neu5Acα2–6]GalNAcα1–), which is the glycotope recognized by Siglec-7, and that CD162 and CD45 are the major carriers of this glycotope on CLL B cells. Analysis of public transcriptomic datasets indicated that the low expression of GCNT1 (encoding core 2 GlcNAc transferase, an enzyme that competes against ST6GalNAc-IV) and high expression of ST6GALNAC4 (encoding ST6GalNAc-IV) in CLL B cells, together enhancing the expression of the disialyl-T glycotope, are associated with poor patient prognosis. Taken together, our results determined the molecular basis of Siglec-7 ligand overexpression that protects CLL B cells from NK cell cytotoxicity and identified disialyl-T as a potential prognostic marker of CLL.

Sialylation regulates migration in chronic lymphocytic leukemia

“…Treatment of resistant CLL cells with neuraminidase could revert this resistance and increase RTX-mediated CDC in sensitive CLL cells. High expression of sialoglycans has been also found in the context of Siglec 7 ligands in CLL 23 . Siglec 7 is a member of immunomodulatory receptors expressed on cells of the immune system, which, upon binding to sialic acids, triggers inhibitory signals that suppress the immune response 32 .…”

“…Siglec 7 is a member of immunomodulatory receptors expressed on cells of the immune system, which, upon binding to sialic acids, triggers inhibitory signals that suppress the immune response 32 . CLL cells express high levels of the disialyl-T antigen, a Siglec 7 ligand, which is synthetized by ST6GalNAc-IV and blocked by core 2 GlcNAc transferase 23 . Importantly, the expression pattern of these two genes that is predictive of high disialyl-T antigen expression (ST6GalNAC4 High and GCNT1 Low ), is associated with a poor prognosis 23 .…”

“…However, it should be highlighted that not only does ibrutinib promote egress of CLL cells but also inhibits re-entry and homing into protective niches by downmodulating pro-adhesive molecules 18,49 , and possibly by inducing their desialylation. Moreover, by inducing desialylation, ibrutinib and similar agents could sensitize circulating CLL cells to the immune system 23,31 . In this context, it will be of interest to examine whether treatment with ibrutinib downmodulates Siglec 7 ligands on CLL cells and sensitize them to NK-mediated cytotoxicity or facilitates RTX-mediated CDC.…”

“…Aberrant sialylation contributes to tumor immune evasion, dissemination and metastasis 21 . Indeed, hypersialylation impairs NK-mediated cytotoxicity in multiple myeloma (MM) 22 and CLL 23 by promoting the binding to sialic acid-binding immunoglobulin-like lectins (Siglecs), a family of inhibitory receptors expressed predominantly by immune cells. Moreover, hypersialylation promotes tumor dissemination and metastasis by modulating the function of different integrins 24 .…”

Natural Killer Cells in Chronic Lymphocytic Leukemia: Functional Impairment and Therapeutic Potential

“…GITRL is also expressed by CLL, and GITR blockade increases the NK activation and cytotoxicity of CLL cells in vitro [ 115 ]. Siglec-7 is an inhibitory glycan receptor expressed in NK cells; its ligands have been detected at increased levels in CLL cells [ 136 ]. Finally, CLL cells express ligands PD-L1, CD200, B7-H3, and HVEM, which are best known for their T cell-suppressive effects but also inhibit NK function [ 114 , 137 , 138 , 139 , 140 ].…”