Serial single-cell profiling analysis of metastatic TNBC during Nab-paclitaxel and pembrolizumab treatment
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PRECLINICAL STUDY
Serial single‑cell profiling analysis of metastatic TNBC during Nab‑paclitaxel and pembrolizumab treatment Jiehui Deng1,5 · Aatish Thennavan2 · Suhagi Shah1 · Ece Bagdatlioglu1 · Natalie Klar1,5 · Adriana Heguy3 · Christian Marier3 · Peter Meyn3 · Yutong Zhang3 · Kristen Labbe1 · Christina Almonte1 · Michelle Krogsgaard4,5 · Charles M. Perou2 · Kwok‑Kin Wong1,5 · Sylvia Adams1,5 Received: 16 June 2020 / Accepted: 8 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose Immunotherapy has recently been shown to improve outcomes for advanced PD-L1-positive triple-negative breast cancer (TNBC) in the Impassion130 trial, leading to FDA approval of the first immune checkpoint inhibitor in combination with taxane chemotherapy. To further develop predictive biomarkers and improve therapeutic efficacy of the combination, interrogation of the tumor immune microenvironment before therapy as well as during each component of treatment is crucial. Here we use single-cell RNA sequencing (scRNA-seq) on tumor biopsies to assess immune cell changes from two patients with advanced TNBC treated in a prospective trial at predefined serial time points, before treatment, on taxane chemotherapy and on chemo-immunotherapy. Methods Both patients (one responder and one progressor) received the trial therapy, in cycle 1 nab-paclitaxel given as single agent, in cycle 2 nab-paclitaxel in combination with pembrolizumab. Tumor core biopsies were obtained at baseline, 3 weeks (after cycle 1, chemotherapy alone) and 6 weeks (after cycle 2, chemo-immunotherapy). Single-cell RNA sequencing (scRNA-seq) of both cancer cells and infiltrating immune cells isolated were performed from fresh tumor core biopsy specimens by 10 × chromium sequencing. Results ScRNA-seq analysis showed significant baseline heterogeneity of tumor-infiltrating immune cell populations between the two patients as well as modulation of the tumor microenvironment by chemotherapy and immunotherapy. In the responding patient there was a population of PD-1high-expressing T cells which significantly decreased after nab-paclitaxel plus pembrolizumab treatment as well as a presence of tissue-resident memory T cells (TRM). In contrast, tumors from the patient with rapid disease progression showed a prevalent and persistent myeloid compartment. Conclusions Our study provides a deep cellular analysis of on-treatment changes during chemo-immunotherapy for advanced TNBC, demonstrating not only feasibility of single-cell analyses on serial tumor biopsies but also the heterogeneity of TNBC and differences in on-treatment changes in responder versus progressor. Keywords Metastatic triple-negative breast cancer · Immunotherapy · Single-cell RNA-seq · Nab-paclitaxel · Anti-PD-1 antibody Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10549-020-05936-4) contains supplementary material, which is available to authorized users. * Kwok‑Kin Wong Kwok‑[email protected] * Sylvia
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