Galectins as Emerging Glyco-Checkpoints and Therapeutic Targets in Glioblastoma

Abstract

Despite recent advances in diagnosis and treatment, glioblastoma (GBM) represents the most common and aggressive brain tumor in the adult population, urging identification of new rational therapeutic targets. Galectins, a family of glycan-binding proteins, are highly expressed in the tumor microenvironment (TME) and delineate prognosis and clinical outcome in patients with GBM. These endogenous lectins play key roles in different hallmarks of cancer by modulating tumor cell proliferation, oncogenic signaling, migration, vascularization and immunity. Additionally, they have emerged as mediators of resistance to different anticancer treatments, including chemotherapy, radiotherapy, immunotherapy, and antiangiogenic therapy. Particularly in GBM, galectins control tumor cell transformation and proliferation, reprogram tumor cell migration and invasion, promote vascularization, modulate cell death pathways, and shape the tumor-immune landscape by targeting myeloid, natural killer (NK), and CD8+ T cell compartments. Here, we discuss the role of galectins, particularly galectin-1, -3, -8, and -9, as emerging glyco-checkpoints that control different mechanisms associated with GBM progression, and discuss possible therapeutic opportunities based on inhibition of galectin-driven circuits, either alone or in combination with other treatment modalities.

The Blessed Union of Glycobiology and Immunology: A Marriage That Worked

“…In this line of thought, many research groups have focused their efforts on disturbing glycoimmune checkpoints, which may act as good targets for cancer treatment [ 142 ]. In this context, the most targeted pathways involve the vascular and immune circuits triggered by both galectins [ 143 , 144 ] and sialoglycan–siglec axis [ 145 , 146 ]. It is important to note that in both cases, there are already successful ongoing clinical trials [ 59 , 146 , 147 ].…”

Glycan-Lectin Interactions as Novel Immunosuppression Drivers in Glioblastoma

“…Indeed, exosomal galectin-9 activity on DCs is TIM3 dependent and knockout of TIM3 in DCs, restore DCs function and activation [ 152 ]. Taken together, these studies suggest that galectin-9/TIM3 can be one of the key mechanisms that sustains immunosuppression in GB TME and it has been proposed as therapeutical intervention for targeting cell–cell interaction and exosomes communication [ 153 , 154 , 155 ].…”

Decoding Strategies to Evade Immunoregulators Galectin-1, -3, and -9 and Their Ligands as Novel Therapeutics in Cancer Immunotherapy

“…For decades, the use of gene editing approaches have allowed researchers to study information on the functional importance of GTs, including galectin–glycan ligand-forming GTs, in cancer, and have been used to model cancer progression and illuminate the pathobiological function and therapeutic promise of glycoconjugate targets in pre-clinical models [ 31 , 104 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 ]. The downregulation of galectins via gene editing methods in combination with chemotherapy has been used to increase therapeutic efficacy against glioblastoma [ 171 ]. However, unless gene editing approaches can specifically target the immune, stromal, or cancer cell of interest and largely avoid impacting normal cellular functions, its clinical utility will be severely compromised.…”