Spatial Immune Infiltrate Mapping Predicts Outcomes in High-Risk Soft Tissue Sarcomas After Neoadjuvant Chemotherapy
In this phase III trial analysis, digital pathology and machine learning were used to quantify the spatial distribution of immune cell populations across four distinct tumour zones in soft tissue sarcomas treated with neoadjuvant chemotherapy. The resulting sarcoma immune index score, particularly from the highest-infiltrate area, independently predicted disease-free and overall survival, demonstrating that chemotherapy modifies the tumour immune microenvironment in a prognostically relevant manner.
The original study
Spatial distribution of tumour immune infiltrate predicts outcomes of patients with high-risk soft tissue sarcomas after neoadjuvant chemotherapy.
- Authors
- Pasquali S, Vallacchi V, Lalli L, Collini P, Barisella M, Romagosa C, et al.
- Journal
- EBioMedicine
- Type
- Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial
- PMID
- 39018755
Original abstract
BACKGROUND: Anthracycline-based neoadjuvant chemotherapy (NAC) may modify tumour immune infiltrate. This study characterized immune infiltrate spatial distribution after NAC in primary high-risk soft tissue sarcomas (STS) and investigate association with prognosis. METHODS: The ISG-STS 1001 trial randomized STS patients to anthracycline plus ifosfamide (AI) or a histology-tailored (HT) NAC. Four areas of tumour specimens were sampled: the area showing the highest lymphocyte infiltrate (HI) at H&E; the area with lack of post-treatment changes (highest grade, HG); the area with post-treatment changes (lowest grade, LG); and the tumour edge (TE). CD3, CD8, PD-1, CD20, FOXP3, and CD163 were analyzed at immunohistochemistry and digital pathology. A machine learning method was used to generate sarcoma immune index scores (SIS) that predict patient disease-free and overall survival (DFS and OS). FINDINGS: Tumour infiltrating lymphocytes and PD-1+ cells together with CD163+ cells were more represented in STS histologies with complex compared to simple karyotype, while CD20+ B-cells were detected in both these histology groups. PD-1+ cells exerted a negative prognostic value irrespectively of their spatial distribution. Enrichment in CD20+ B-cells at HI and TE areas was associated with better patient outcomes. We generated a prognostic SIS for each tumour area, having the HI-SIS the best performance. Such prognostic value was driven by treatment with AI. INTERPRETATION: The different spatial distribution of immune populations and their different association with prognosis support NAC as a modifier of tumour immune infiltrate in STS. FUNDING: Pharmamar; Italian Ministry of Health [RF-2019-12370923; GR-2016-02362609]; 5 × 1000 Funds-2016, Italian Ministry of Health; AIRC Grant [ID#28546].