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Establishment and Characterization of Patient-Derived Xenograft Models of Anaplastic Thyroid Carcinoma and Head and Neck Squamous Cell Carcinoma
Published on: June 2, 2023
Targeting SIGLEC15 as an emerging immunotherapy for anaplastic thyroid cancer
Lisha Bao1, Ying Li2, Xiaoping Hu3
1Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, 310014, Hangzhou, China.
Abstract:
Anaplastic thyroid carcinoma (ATC) is the most aggressive subtype of thyroid cancer with few effective therapies. Though immunotherapies such as targeting PD-1/PD-L1 axis have benefited patients with solid tumor, the druggable immune checkpoints are quite limited in ATC. In our study, we focused on the anti-tumor potential of sialic acid-binding Ig-like lectins (Siglecs) in ATC. Through screening by integrating microarray datasets including 216 thyroid-cancer tissues and single-cell RNA-sequencing, SIGLEC family members CD33, SIGLEC1, SIGLEC10 and SIGLEC15 were significantly overexpressed in ATC, among which SIGLEC15 increased highest and mainly expressed on cancer cells. SIGLEC15high ATC cells are characterized by high expression of serine protease PRSS23 and cancer stem cell marker CD44. Compared with SIGLEC15low cancer cells, SIGLEC15high ATC cells exhibited higher interaction frequency with tumor microenvironment cells. Further study showed that SIGLEC15high cancer cells mainly interacted with T cells by immunosuppressive signals such as MIF-TNFRSF14 and CXCL12-CXCR4. Notably, treatment of anti-SIGLEC15 antibody profoundly increased the cytotoxic ability of CD8+ T cells in a co-culture model and zebrafish-derived ATC xenografts. Consistently, administration of anti-SIGLEC15 antibody significantly inhibited tumor growth and prolonged mouse survival in an immunocompetent model of murine ATC, which was associated with increase of M1/M2, natural killer (NK) cells and CD8+ T cells, and decrease of myeloid-derived suppressor cells (MDSCs). SIGLEC15 inhibited T cell activation by reducing NFAT1, NFAT2, and NF-κB signals. Blocking SIGLEC15 increased the secretion of IFN-γ and IL-2 in vitro and in vivo. In conclusion, our finding demonstrates that SIGLEC15 is an emerging and promising target for immunotherapy in ATC.
Insights
Anaplastic thyroid carcinoma (ATC) is aggressive, but targeting SIGLEC15 shows promise. Blocking SIGLEC15 enhances T cell activity and inhibits tumor growth, offering a new immunotherapy approach for ATC.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Anaplastic thyroid carcinoma (ATC) is a highly aggressive thyroid cancer with limited treatment options.
- Existing immunotherapies targeting PD-1/PD-L1 have shown limited efficacy in ATC due to restricted druggable immune checkpoints.
- Sialic acid-binding Ig-like lectins (Siglecs) represent a potential area for novel immunotherapeutic strategies in ATC.
Purpose of the Study:
- To investigate the anti-tumor potential of Siglecs in anaplastic thyroid carcinoma.
- To identify specific Siglec family members overexpressed in ATC and assess their role in tumor progression and immune evasion.
Main Methods:
- Integrated analysis of microarray datasets (216 thyroid-cancer tissues) and single-cell RNA-sequencing to screen for Siglec expression.
- Characterization of SIGLEC15-high ATC cells and their interactions with the tumor microenvironment.
- In vitro and in vivo experiments using anti-SIGLEC15 antibody treatment in co-culture models, zebrafish xenografts, and immunocompetent murine ATC models.
Main Results:
- SIGLEC15 was significantly overexpressed in ATC, particularly on cancer cells, and associated with PRSS23 and CD44 expression.
- SIGLEC15-high ATC cells exhibited increased interactions with tumor microenvironment cells, including T cells, via immunosuppressive signals (MIF-TNFRSF14, CXCL12-CXCR4).
- Anti-SIGLEC15 antibody treatment enhanced CD8+ T cell cytotoxicity, inhibited tumor growth, prolonged survival in mice, and modulated immune cell populations (increased M1/M2, NK, CD8+ T cells; decreased MDSCs).
Conclusions:
- SIGLEC15 is a promising therapeutic target for anaplastic thyroid carcinoma immunotherapy.
- Blocking SIGLEC15 can overcome immune suppression by enhancing T cell activation and effector functions.
- Targeting SIGLEC15 represents a novel strategy to improve treatment outcomes for patients with ATC.
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