Reactivating cancer immunity: the role of siglec-15
T lymphocytes are key components of the immune system, as they play a crucial role in identifying and responding to foreign or harmful entities such as bacteria. Cancer cells have developed sophisticated evasion mechanisms, allowing them to disguise themselves as normal cells. One such mechanism involves an abundance of sialic acid on the cancer cell surface, a simple sugar that decorates the caps of membrane glycoproteins. This prevents T cell activation and facilitates immune escape.
Sialic acid recognition by T cells
Undertaken with the support of the Marie Skłodowska-Curie Actions (MSCA) programme, the CD28 project aimed to understand which receptors are involved in the recognition of sialic acid and whether they activate or suppress T cell responses. T cell activity is regulated by a balance of co-stimulatory and inhibitory receptors. CD28 is one of the most crucial co-stimulatory receptors, providing the second activation signal necessary for T cell proliferation. Conversely, inhibitory receptors such as CTLA-4 and PD-1 suppress T cell responses, leading to immune tolerance and exhaustion in chronic infections and in cancer. “We wanted to investigate how sialic acid-containing glycans interact with CD28, and to develop molecular strategies to counteract T cell inhibition,” explain project investigators, Pablo Valverde, June Ereño-Orbea, and Jesús Jiménez-Barbero. Previous work had indicated that CD28 co-activation improves when the sialic acid residues present all over the cell surface are enzymatically removed. The project initially sought to establish whether hypersialylated antigens directly inhibited CD28 activation, which could explain why T cells become tolerant in tumour environments. Structural studies were conducted to determine the molecular basis of sialic acid recognition by CD28. “As we observed no binding interactions between CD28 and sialylated glycans, we had to rethink our approach and investigate alternative inhibitory pathways that suppress T cell activity,” states Jiménez-Barbero.
Siglec-15: putative immunotherapy target?
Researchers shifted their focus to Siglec-15 next, which is a relatively unknown member of the Siglec family. Siglec-15 is expressed on tumour-associated macrophages and plays a key role in suppressing antigen-specific T cell responses within the tumour microenvironment. Structural studies with the glycan library revealed new insights into the ligand specificity of Siglec-15, providing a foundation for drug development. Siglec-15 showed broad ligand selectivity and recognised sialic acid in many arrangements, favouring its inhibitory action on T cells.
Clinical impact and future directions
The CD28 project focused on early-stage drug discovery by identifying molecular targets that could inform future therapeutic development. Project findings highlight the potential of Siglec-15 inhibition as an alternative immunotherapeutic strategy that could be further combined with antibody treatment to counteract tumour-driven immune suppression and enhance T cell responses. The project also demonstrated the feasibility of developing synthetic ligands to block Siglec-15, a crucial step towards novel cancer immunotherapies. Preliminary data suggest enhanced activity with these modified ligands, opening new possibilities for structure-based drug design. By leveraging AI-driven tools for protein and drug design, researchers aim to accelerate the development of high-affinity modulators targeting Siglec-15. “Overall, we laid the groundwork for future advancements in cancer immunotherapy, offering new hope for more effective and widely accessible treatments,” conclude Ereño-Orbea and Jiménez-Barbero.
Keywords
CD28, Siglec-15, cancer, sialic acid, T cells, immunotherapy