Siglec15 Regulation of Immune Suppressive Microenvironment in Sarcoma
Soft tissue sarcomas present a significant challenge in medical research, being inadequately explored and often resistant to conventional treatments. Among the various subtypes, undifferentiated pleomorphic sarcoma, a major subtype of adult sarcomas, is particularly understudied, with 50% of patients developing fatal lung metastases and a median survival of less than 15 months.
To address this, understanding how sarcoma cells develop and spread to other organs is critical for developing targeted treatments. Employing a primary mouse model initiated with gene mutations commonly found in human sarcomas, co-evolving with immune cells, provides a unique platform for both studying sarcoma biology and conducting preclinical trials for effective therapies, such as immunotherapy. This model becomes indispensable given the limited availability of sarcoma patients for basic and translational research.
A small percentage of undifferentiated pleomorphic sarcoma cases responding to the immunotherapy called anti-PD-1 immune checkpoint blockade, but most are resistant. Therefore, an urgent unmet need is to develop more effective immunotherapies for this devastating disease, which lags behind other common cancers. One main reason is that current primary models used in research lack genetic relevance to human undifferentiated pleomorphic sarcomas or are unsuitable for testing immunotherapies.
In our study, we introduce a novel mouse model established in our lab, the first to genetically mimic human undifferentiated pleomorphic sarcoma. This model allows us to systematically investigate how Bap1 gene mutations regulate sarcoma development and metastasis to the lung. Also, it enables the examination of immune cell infiltration, offering insights into potential strategies for immunotherapies and combination therapy.
Using our mouse model, we identified Siglec15 transmembrane protein as a potential immunotherapy target for undifferentiated pleomorphic sarcoma. Preliminary research has identified that high levels of Siglec15 expression are associated with poor survival in sarcoma, and Siglec15 is drastically upregulated in both human and mouse undifferentiated pleomorphic sarcoma. Ablation of Siglec15 induced an immune response and resulted in tumor growth inhibition. Additionally, the percentage of immune cells dramatically increased in tumors upon deletion of Siglec15. Therefore, we propose to test our hypothesis that a Siglec15 antagonist alone or combined with anti-PD-1 blockade can suppress the growth and metastasis of undifferentiated pleomorphic sarcoma.
The Siglec15 antagonist proposed in the study is currently being tested in human clinical trials. However, sarcoma patients are not included in the trials, and no prior research has explored the role of Siglec15 in sarcomas. Thus, our results may pave the way for moving a Siglec15 antagonist from bench to bedside, potentially treating patients with this challenging disease within two years.