Abstract
Tumour-infiltrating lymphocytes (TILs) in breast cancer (BC) provide prognostic and predictive information. The aim of this study was to assess the spatial and temporal heterogeneity of TILs in BC and its relationship with immune cell subtypes. Immunohistochemically defined immune cell subtypes, i.e. those expressing T-cell markers (CD3, CD8, and FOXP3), a B-cell marker (CD20) and a histiocytic marker (CD68), were evaluated in a large series (n=1165) of invasive BCs. A subset of full-face haematoxylin and eosin (H&E)-stained slides were examined for TILs heterogeneity within primary tumours and the corresponding local recurrent carcinomas to investigate spatial and temporal TILs heterogeneity. H&E-stained sections from multiple tumour blocks (three or four blocks per case) representing different tumour areas were evaluated to assess TILs interslide heterogeneity and intraslide heterogeneity. Both average stromal TILs (AV-TILs) and hotspot stromal TILs (HS-TILs) were assessed. AV-TILs showed associations with all immune cell subtypes; however, CD3+ cells constituted the main component (mean number of CD3+ was 55), whereas CD20+ cells constituted the smallest component (mean number of CD20 was 13). There was no significant statistical difference between TILs across tumour blocks of the same case (P=0.251 for AV-TILs and P=0.162 for HS-TILs). Triple-negative breast cancer (TNBC) showed higher TILs percentage than other BC subtypes (P<0.001). High AV-TILs, CD3+ cells, CD8+ cells and CD20+ cells were associated with longer survival in TNBC patients (P<0.05). High AV-TILs in recurrent tumours showed a significant association with shorter post-recurrence survival (P=0.004). Despite the heterogeneity of immune cell type components, average TILs in one full-face H&E-stained section reliably represent TILs in the whole tumour. TILs were associated with outcome in TNBC patients, as well as having prognostic significance for recurrent tumours.
Highlights
Breast cancer (BC) microenvironment comprises a complex mixture of cell types including immune modulating cells that provide an opportunity for therapeutic modulation [1, 2]
Tumour-infiltrating lymphocytes (TILs) were associated with outcome in Triple negative breast cancer (TNBC) as well as provided prognostic significance in recurrent tumour
To assess specific sub-population of TILs, the expression of lymphocytic biomarkers; CD3, CD8, CD20, and FOXP3 and macrophage/histiocytic biomarker; CD68 were evaluated in the whole cohort (n=1,165)
Summary
Breast cancer (BC) microenvironment comprises a complex mixture of cell types including immune modulating cells that provide an opportunity for therapeutic modulation [1, 2]. The contribution of each immune cell subtype to the prognostic value of overall TILs assessed on H&E slides remains unclear. The role of histiocytes, as a component of the immune cells in BC, and whether they contribute prognostic value and should be included in TILs assessment in BC has not been resolved. Ii) Contribution of various immune cell subtypes, as molecularly defined, to overall TILs and their prognostic value were evaluated. H&E stained sections from multiple tumour blocks (3-4 blocks per case) representing different tumour areas were evaluated to assess TILS inter-slide heterogeneity as well as intra-slide heterogeneity. Both average (AV-TILs) and hotspot (HS-TILs) stromal TILs were assessed. High AV-TILs in recurrent tumours showed significant association with shorter post-recurrence survival (p=0.004)
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