Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy (original) (raw)

hile antigen is required for T cells to initiate the activation process, the specific ligand-receptor interactions on the cell surface, such as the molecules in the B7-CD28 family and the tumor necrosis factor superfamily, transmit either positive or negative signals to T cells and determine the direction and fate of the immune response 1-3. Manipulation by antagonizing or agonizing these signals selectively amplifies immune responses and eliminates tumors 4-7. In addition to the magnitude of the immune response, the geographic location where the response is generated and executed is critical in the context of cancer immunotherapy. Selective amplification of anti-tumor immunity in the TME has led to highly efficacious cancer immunotherapies without excessive side-effects 8,9. A conceptually important advance in cancer immunology in recent years is the presence of adaptive resistance mechanisms in the TME to prevent the execution of tumor immunity. For example, B7-H1 (CD274, PD-L1) 10,11 is selectively induced in the TME, predominantly by interferon-gamma (IFN-γ) from tumor-infiltrating T-lymphocytes, which in turn initiates a series of events including the engagement of PD-1 on T cells, transmission of apoptosis and exhaustion signals that eventually leads to the dysfunction of T cells, a process collectively called adaptive resistance 7,12,13. Blockade of the B7-H1/PD-1 pathway by specific mAbs to B7-H1 or PD-1 (anti-PD therapy) prevents the dysfunction of T cells and selectively restores immune responses in the TME 7-9. This strategy, collectively called normalization cancer immunotherapy 14 , is remarkably effective for the treatment of cancer, as demonstrated clinically by the regression of a broad spectrum of advanced cancers and by significant survival benefits in patients 8,15,16. Immune evasion mechanisms in the TME of advanced human cancers are highly heterogeneous. On the basis of our recent definitions used to classify tumor immunity in the microenvironment (TIME), the B7-H1/PD-1 pathway is responsible for dysfunctional immunity in fewer than 40% of human solid tumors 12,15,17. Ample evidence supports that, in addition to the upregulation of B7-H1, many other molecular or cellular mechanisms can also contribute to dysfunctional immunity in the TME. These mechanisms include, but are not limited to, a lack of sufficient immune cell infiltration, accumulation of regulatory T cells, the presence of tumor-associated macrophages (TAMs) and myeloid-derived suppressive cells, as well as upregulation of suppressive molecules, cytokines, metabolites and downregulation of immune stimulatory molecules 18,19. Many of these mechanisms, however, may not be selective for the TME and, therefore, manipulation of these pathways could lead to a broad activation of the immune system with the risk of autoimmune toxicities 8,20. The current success of anti-PD therapy highlights the importance of restoring defective immune responses in the TME as a principle for normalization cancer immunotherapy 14. Siglec-15 was originally identified as one of the Siglec gene family members with a characteristic sialic acid-binding immunoglobulin-type lectin structure 21. While the role of Siglec-15 in osteoclast differentiation and bone remodeling has been reported 22-25 , its immunological function remains largely unknown. We demonstrate that the expression of Siglec-15 is normally limited to cells in myeloid lineage but can be upregulated in many human cancers. Employing a newly developed genome-scale T cell activity array (TCAA), mice with whole-body or lineage-specific gene ablation and specific mAbs, we discovered Siglec-15 as an immune suppressive molecule largely operating in the TME and is non-redundant to the B7-H1/PD-1 pathway. Results High-throughput screening of the human transmembrane proteome for the discovery of T cell activity modulators. We constructed a high-throughput functional screening system (TCAA) to identify cell surface modulators of T cell activities in vitro (Fig. 1a). The TCAA includes over 6,500 human genes encoding >90% of