In recent years, the immune system has been shown to play an important role in the development and progression of cancer. In various malignancies, the prognostic relevance of TILs has been shown. STS are a heterogeneous group of rare mesenchymal malignancies. Known prognostic factors for STS include size, localization and grading. The aim of the study was to evaluate the prognostic significance of TILs and different T-cell subsets for survival.
Tissue microarrays (TMA) of tumor samples of STS patients, treated in the EORTC 62961 Phase III trial (Lancet Oncol. 2010), were assessed for TILs, counted in standard HE stainings. Additionally, immuno-stainings for CD3 (pan-T-cell marker), CD8 (cytotoxic T cells), FOXP3 (regulatory T cells) and PD-1 (T-cell activation/exhaustion) were evaluated. For 109 patients, 137 biopsies were available before (84 samples) or after (53 samples) NAC ± RHT. Paired tumor samples (before and after NAC ± RHT), were available for 28 patients. Outcome was compared using Kaplan-Meier and Cox estimations.
Before initiation of NAC, TIL counts were significantly higher in poorly differentiated G3 than in G2 tumors. However, NAC lead to a significant increase in TIL counts, and the association with grading was no longer evident after NAC ± RHT. FOXP3 cell counts were significantly decreased after NAC ± RHT. Local progression-free survival (LPFS) and disease-free survival (DFS) were significantly enhanced for patients with high TIL counts (>5/TMA) after completion of NAC ± RHT. Differences in tumor infiltration of CD3, CD8, FOXP3, and PD-1 positive cells were not associated with significant differences in LPFS or DFS.
High TIL counts before start of NAC are associated with poor tumor differentiation in STS. Neoadjuvant treatment increases TILs and leads to significant changes in the distribution of T-cell subsets within the tumor. High TIL counts in response to therapy may be predictive for local control and survival in STS.
Clinical trial identification
Legal entity responsible for the study
EORTC Soft-Tissue-Bone-Sarcoma-Group, European Society for Hyperthermic Oncology
Deutsche Krebshilfe (M99/94/Wi II, 70-I702-Wi II), Helmholtz Association (VH-VI-140), EORTC 62961, ESHO RHT-95, and NIH P01 CA42745
R. Issels: honorary fee and travel support by PharmaMar and Pyrexar. All other authors have declared no conflicts of interest.