MDR1-expressing CD4 + T cells with Th1.17 features resist to neoadjuvant chemotherapy and are associated with breast cancer clinical response

作者：Anthony Di Roio, Margaux Hubert, Laurie Besson, Marion Bossennec, Céline Rodriguez, Yenkel Grinberg‐Bleyer, Guilhem Lalle, Lyvia Moudombi, Raphaël Schneider, Cyril Dégletagne, Isabelle Treilleux, Daniel Campbell, Séverine Metzger, Thomas Duhen, Olivier Trédan, Christophe Caux, Christine Ménétrier‐Caux · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2023 · DOI：10.1136/jitc-2023-007733 · 被引用次数：10 · 研究领域：Cancer Immunotherapy and Biomarkers、Drug Transport and Resistance Mechanisms、Immunotherapy and Immune Responses

Background Multidrug resistance-1 (MDR1) transporter limits the intracellular accumulation of chemotherapies (paclitaxel, anthracyclines) used in breast cancer (BC) treatment. In addition to tumor cells, MDR1 is expressed on immune cell subsets in which it confers chemoresistance. Among human T cells, MDR1 is expressed by most CD8 + T cells, and a subset of CD4 + T helper (Th) cells. Here we explored the expression, function and regulation of MDR1 on CD4 + T cells and investigated the role of this population in response to neoadjuvant chemotherapy (NAC) in BC. Methods Phenotypic and functional characteristics of MDR1 + CD4 Th cells were assessed on blood from healthy donors and patients with BC by flow cytometry. These features were extended to CD4 + Th cells from untreated breast tumor by flow cytometry and RNA-sequencing (RNA-seq). We performed in vitro polarization assays to decipher MDR1 regulation on CD4 Th cells. We evaluated in vitro the impact of chemotherapy agents on MDR1 + CD4 + Th cells. We analyzed the impact of NAC treatment on MDR1 + CD4 + Th cells from blood and tumors and their association with treatment efficacy in two independent BC cohorts and in a public RNA-seq data set of BC tumor biopsies before and after NAC. Finally, we performed single cell (sc) RNAseq of blood CD4 + memory T cells from NAC-treated patients and combined them with an scRNAseq public data set. Results MDR1 + CD4 Th cells were strongly enriched in Th1.17 polyfunctional cells but also i...