Dissecting immunological effects of neoadjuvant therapies in primary high-risk soft tissue sarcomas

Patients with high-risk primary soft tissue sarcomas (STS) of the extremities or trunk wall often receive anthracycline-based chemotherapy before (neoadjuvant) or after (adjuvant) surgery to reduce the risk of recurrence. While this strategy improves outcomes in selected cases, long-term results remain suboptimal, with \~50% of patients experiencing disease relapse within five years. 

Emerging evidence suggests that anthracyclines not only exert cytotoxic effects but may also modulate the tumour immune microenvironment. In other solid tumours, such as breast cancer, anthracyclines have enhanced the efficacy of immune checkpoint inhibitors (ICIs) like pembrolizumab. Similar trends have been observed in metastatic STS, where the combination of doxorubicin and ICIs showed improved response rates compared to ICIs alone. However, immune responsiveness varies substantially across STS histological subtypes, likely due to differences in tumour biology, mutational burden, and immune infiltrate. 

Neoadjuvant anthracycline-based chemotherapy induces favourable immunomodulatory effects in certain high-risk STS subtypes. These effects may enhance sensitivity to ICIs. Therefore, integrating ICIs into perioperative treatment could improve disease control and survival in selected STS patients. 

The aims of the Projects are:  

1. Characterise tumour immune microenvironment pre- and post-neoadjuvant therapy 
2. Monitor systemic immune changes and circulating tumour DNA (ctDNA) 
3. Test ICI efficacy in ex vivo STS models 

Expected Outcomes: 

This study aims to define immune signatures and mechanisms of action underlying the response to neoadjuvant therapies and to identify subsets of STS patients who may benefit from combined chemo-immunotherapy strategies. By integrating tissue and liquid biopsy data with functional ex vivo studies, this research may inform future clinical trial design and contribute to a more personalised therapeutic approach in high-risk STS.