Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple-negative breast cancer

TLDR

In triple‑negative breast cancer, the benefit of combining chemotherapy with checkpoint inhibitors remains unclear. The study aims to investigate immune cell dynamics in advanced TNBC patients treated with paclitaxel alone or with atezolizumab using single‑cell RNA‑ and ATAC‑sequencing. Single‑cell RNA‑ and ATAC‑sequencing were performed on samples from 22 patients to profile immune cell subsets and their transcriptional and chromatin accessibility changes. High baseline CXCL13⁺ T cells, associated with pro‑inflammatory macrophages, predict effective responses to atezolizumab, and their levels rise with combination therapy while falling with paclitaxel alone, underscoring the importance of CXCL13⁺ T cells and the potential negative impact of paclitaxel on anti‑PD‑L1 efficacy.

Abstract

In triple-negative breast cancer (TNBC), the benefit of combining chemotherapy with checkpoint inhibitors is still not very clear. We utilize single-cell RNA- and ATAC-sequencing to examine the immune cell dynamics in 22 patients with advanced TNBC treated with paclitaxel or its combination with the anti-PD-L1 atezolizumab. We demonstrate that high levels of baseline CXCL13+ T cells are linked to the proinflammatory features of macrophages and can predict effective responses to the combination therapy. In responsive patients, lymphoid tissue inducer (LTi) cells, follicular B (Bfoc) cells, CXCL13+ T cells, and conventional type 1 dendritic cells (cDC1) concertedly increase following the combination therapy, but instead decrease after paclitaxel monotherapy. Our data highlight the importance of CXCL13+ T cells in effective responses to anti-PD-L1 therapies and suggest that their reduction by paclitaxel regimen may compromise the clinical outcomes of accompanying atezolizumab for TNBC treatment.