Single-cell spatial analysis can predict response to neoadjuvant immunotherapy

A next-generation technology that allows the study of protein expression at the single-cell level and the location of the cells to be within the tumour microenvironment was feasible and provided information on the benefit of adding the immune checkpoint inhibitor atezolizumab to chemotherapy as neoadjuvant treatment for patients with early high-risk and locally advanced triple-negative breast cancer (TNBC).

Immune checkpoint inhibitors are effective in early and advanced TNBC. However, only a minority of patients benefit from it, making precision immuno-oncology a major unmet need. Imaging mass cytometry enables high dimensional tissue imaging at subcellular resolution for assessment of TNBC ecosystems, providing information on cell type composition, functional status, and spatial organisation. Dr Giampaolo Bianchini (Ospedale San Raffaele, Italy) and colleagues investigated whether imaging mass cytometry could assist in the identification of ideal candidates for this therapeutic approach. They performed imaging mass cytometry analysis in the context of the phase 3 NeoTRIPaPDL1 trial (NCT02620280), which was designed to evaluate the addition of atezolizumab to the chemotherapeutics carboplatin and nab-paclitaxel as neoadjuvant therapy in patients with early high-risk and locally advanced TNBC.

Forty-three protein-spanning cancer cells and the tumour microenvironment were assessed on pre-treatment, formalin-fixed, paraffin-embedded biopsies of 243 of the 280 enrolled patients. For each sample, 3 high-dimensional images were generated that encompassed the tumour, tumour-stroma interface, and adjacent stroma. The association of protein expression was assessed for epithelial and tumour-microenvironment cells, cell phenotypes, and the spatial tissue organisation with pathological complete response rate. Dr Bianchini presented the results [1].

By supervised clustering, 37 cell phenotypes were defined. PD-L1-positive tumours, high stromal tumour-infiltrating lymphocytes, and TNBC type were characterised by extreme heterogeneity and unique cell-type and spatial tumour microenvironment composition. Bulk protein expression analysis delivered only limited predictive information because it does not consider the cell compartment in which each protein is expressed. Several biomarkers demonstrated a significant association with pathological complete response rate. For example, high density of PD-L1-positive and IDO-positive antigen presenting cells, as well as high density of CD56-positive epithelial cells, was associated with higher pathological complete response rate in patients who received atezolizumab plus chemotherapy, but not in patients who only received chemotherapy (OR 4.5; p<0.001). In addition, high degree of spatial connectivity between epithelial cells and specific tumour-microenvironment cells correlated with a significant increase in the pathological complete response rate after atezolizumab.

“Our results demonstrate that imaging mass cytometry is feasible in a large, randomised trial and provides a comprehensive overview of TNBC at a single-cell level with special resolution, paving the way for its broad implementation in cancer research to aid precision immunology,” concluded Bianchini. “Information on spatial data and on the interactions among specific cells in the tumour microenvironment might be informative about the benefit provided by an immune checkpoint inhibitor such as atezolizumab in addition to chemotherapy. However, all these findings will require independent validation.”

1. Bianchini G, et al. Single-cell spatial analysis by imaging mass cytometry and immunotherapy response in triple-negative breast cancer (TNBC) in the NeoTRIPaPDL1 trial. GS1-00, SABCS 2021 Virtual Meeting, 7–10 December.

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Posted on 31 January, 202225 March, 2024