CASSIS · A single-cell atlas of human soft tissue sarcoma ecosystems with focus on mechanisms of immune evasion

A single-cell atlas of human soft tissue sarcoma ecosystems with focus on mechanisms of immune evasion

Sarcomas are rare cancers with an incidence of less than 6 per 100,000 persons per year. More than 150 different subtypes have been described based on histologic features, i.e., how the tumor tissue looks under the microscope upon pathology assessment. Sarcomas affect all age groups and are more frequent in children, adolescents, and young adults than in older adults (Ferrari et al., 2011). The standard treatment includes surgery, radiation, and chemotherapy. Compared with other cancers, this represents a rather limited therapy spectrum. While these approaches are effective in some patients, those who do not respond currently have few other therapy options. This results in a poor prognosis and the loss of many years of life, in particular in the young patient population. New treatment approaches have been developed that target the tumor microenvironment, which consists of diverse non-cancerous cells that interact with the tumor to either support or inhibit its growth. Together, these interactions establish a tumor ecosystem with dependencies and vulnerabilities. One aim of targeted therapies is to interrupt tumor nutrient and oxygen supplies needed for growth, e.g., by blocking the development of new blood vessels in the ecosystem (Cren et al., 2020). Another aim is to activate an anti-tumor immune attack through immunomodulatory therapeutics to eliminate the cancer cells (Anastasiou et al., 2023). Among the latter, immune checkpoint inhibitor antibodies have become a mainstay of therapy across multiple cancer types (Sharma et al., 2023). The application of such treatment approaches to sarcoma patients is under extensive investigation by basic research and in clinical trials, but so far, success rates varied greatly between patients and sarcoma subtypes (Anastasiou et al., 2023). This is, on the one hand, due to our limited understanding of sarcoma tumor ecosystems, i.e., their specific cellular composition, dependencies, and vulnerabilities. On the other hand, due to the lack of molecular biomarkers that can guide patient selection for specific targeted therapies. The overall aim of this EU-funded project was to fill this knowledge gap and reach a better understanding of sarcoma ecosystems. Specifically, we aimed to comprehensively characterize the cellular diversity and tumor-immune interactions within ecosystems of multiple sarcoma subtypes at the single-cell level and with spatial resolution. For this, we designed experimental protocols and used a combination of state-of-the-art single-cell technologies. The specific objectives were: Objective 1: Characterizing the cellular diversity and tumor-immune interactions in sarcoma ecosystems using single-cell transcriptomics and cell surface proteomics. Objective 2: Profiling the sarcoma immune environment with single-cell spatial resolution. Objective 3: Functionally assessing candidate tumor-immune interactions in vitro.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз