A next-generation technology allows the study of protein expression at the single-cell level and the location of the cells within the tumor microenvironment (TME). In the NeoTRIPaPDL1 trial, it 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, making precision immune-oncology a major unmet need. Biomarkers are urgently needed to help identify the patients who will benefit the most from the addition of immunotherapy, and those who will do well just with chemotherapy. Imaging mass cytometry (IMC) enables high-dimensional tissue imaging at subcellular resolution for assessment of TNBC ecosystems, providing information on cell type composition, functional status, and spatial organization. Dr. Giampaolo Bianchini (Ospedale San Raffaele, Italy) and colleagues investigated whether IMC could assist in the identification of ideal candidates for this therapeutic approach. They performed IMC analysis in the context of phase 3 NeoTRIPaPDL1 trial (NCT02620280), which was designed to evaluate the addition of atezolizumab to chemotherapy (carboplatin and nab-paclitaxel) as neoadjuvant therapy in patients with early high-risk and locally advanced TNBC. A total of 43 proteins spanning cancer cells and the TME were assessed on pre-treatment FFPE biopsies of 243 of the 280 enrolled patients. For each sample, 3 high-dimensional images were generated that encompassed the tumor, tumor-stroma interface, and adjacent stroma. The association of protein expression on tumor and TME cells, cell phenotypes, and spatial tissue organization with pathological complete response rate (pCR) was investigated. By supervised clustering, 37 cell phenotypes were defined. PD-L1-positive tumors, high stromal tumor-infiltrating lymphocytes, and TNBC type were characterized by extreme heterogeneity and unique cell type and spatial TME composition. Bulk protein expression analysis delivered only limited predictive information because it does not take into account the cell compartment in which each protein is expressed. Several biomarkers demonstrated a significant association with pCR. 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 pCR in patients who received atezolizumab plus chemotherapy but not in patients who only received chemotherapy. In addition, a high degree of spatial connectivity between epithelial cells and specific TME cells correlated with a significant increase in the PCR rate after atezolizumab. “Our results demonstrate that IMC is feasible in a large, randomized trial and provides a comprehensive overview of TNBC at a single-cell level with spatial 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 TME might be very 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. SABCS 2021 Virtual Meeting, abstract GS1-00.

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