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Reshaping the tumor microenvironment by degrading glycoimmune checkpoints Siglec-7 and -9
Chao Wang1,2, Yingqin Hou1, Jaroslav Zak3
1Department of Molecular and Cellular Biology, The Scripps Research Institute, California, United States.
Abstract:
Cancer treatment has been rapidly transformed by the development of immune checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1. However, many patients fail to respond, especially those with an immunosuppressive tumor microenvironment (TME), suggesting the existence of additional immune checkpoints that act through orthogonal mechanisms. Sialic acid-binding immunoglobulin-like lectin (Siglec)-7 and -9 are newly designated glycoimmune checkpoints that are abundantly expressed by tumor-infiltrating myeloid cells. We discovered that T cells express only basal levels of Siglec transcripts; instead, they acquire Siglec-7 and -9 from interacting myeloid cells in the TME via trogocytosis, which impairs their activation and effector function. Mechanistically, Siglec-7 and -9 suppress T cell activity by dephosphorylating T cell receptor (TCR)-related signaling cascades. Using sulfur fluoride exchange (SuFEx) click chemistry, we developed a ligand that binds to Siglec-7 and -9 with high-affinity and exclusive specificity. Using this ligand, we constructed a Siglec-7/9 degrader that targets membrane Siglec-7 and -9 to the lysosome for degradation. Administration of this degrader induced efficient Siglec degradation in both T cells and myeloid cells in the TME. We found that Siglec-7/9 degradation has a negligible effect on macrophage phagocytosis, but significantly enhances T cell anti-tumor immunity. The degrader, particularly when combined with anti-CTLA-4, enhanced macrophage antigen presentation, reshaped the TME, and resulted in long-lasting T cell memory and excellent tumor control in multiple murine tumor models. These findings underscore the need to consider exogenous checkpoints acquired by T cells in the TME when selecting specific checkpoint blockade therapy to enhance T cell immunity.
Insights
New glycoimmune checkpoints, Siglec-7 and -9, are acquired by T cells from myeloid cells in the tumor microenvironment. Degrading these Siglecs enhances T cell anti-tumor immunity, especially with anti-CTLA-4 therapy.
Area of Science:
- Immunology
- Cancer Biology
- Drug Development
Background:
- Current cancer immunotherapies like checkpoint inhibitors (CTLA-4, PD-1/PD-L1) show limited efficacy in patients with immunosuppressive tumors.
- This suggests the existence of additional immune checkpoints operating via distinct mechanisms within the tumor microenvironment (TME).
- Sialic acid-binding immunoglobulin-like lectins (Siglecs), specifically Siglec-7 and -9, are identified as novel glycoimmune checkpoints abundant on myeloid cells in the TME.
Purpose of the Study:
- To investigate the role of Siglec-7 and -9 in T cell function within the TME.
- To develop a novel therapeutic strategy targeting these glycoimmune checkpoints.
- To evaluate the efficacy of Siglec-7/9 degradation in combination with existing immunotherapies.
Main Methods:
- Investigated Siglec transcript expression in T cells and their acquisition from myeloid cells via trogocytosis.
- Utilized sulfur fluoride exchange (SuFEx) click chemistry to develop a high-affinity, specific ligand for Siglec-7 and -9.
- Engineered a Siglec-7/9 degrader to induce lysosomal degradation of these checkpoints.
- Assessed the impact of Siglec degradation on T cell activation, effector function, macrophage activity, and anti-tumor immunity in murine models.
Main Results:
- T cells acquire Siglec-7 and -9 from myeloid cells in the TME through trogocytosis, suppressing T cell receptor (TCR) signaling and effector function.
- A novel Siglec-7/9 degrader effectively removed these checkpoints from T cells and myeloid cells.
- Siglec-7/9 degradation enhanced T cell anti-tumor immunity without affecting macrophage phagocytosis.
- Combination therapy with the Siglec-7/9 degrader and anti-CTLA-4 improved antigen presentation, reshaped the TME, and induced durable anti-tumor responses and memory.
Conclusions:
- Exogenously acquired Siglec-7 and -9 represent critical immune checkpoints that impair T cell anti-tumor activity.
- Targeting these acquired checkpoints with degraders offers a promising therapeutic strategy to enhance T cell-mediated immunity.
- Combined targeting of Siglec-7/9 and CTLA-4 demonstrates significant potential for improving cancer treatment outcomes.
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