Single-Cell Transcriptomics Reveals Immune Landscape Dynamics in Metastatic Hormone Receptor–Positive Breast Cancer Treated with Abemaciclib and Endocrine Therapy

PURPOSE: In advanced estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer, the combination of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) with endocrine therapy (ET) is the standard of care for treatment in the first-line setting. Although CDK4/6is were initially developed to induce cell-cycle arrest, it is evident that CDK4/6is also have the potential to regulate the tumor immune microenvironment. In this study, we characterize the baseline immune landscape and the immunomodulatory effects of abemaciclib and ET in advanced breast cancer tumors. EXPERIMENTAL DESIGN: We used single-cell RNA sequencing of CD45-enriched cells to investigate the effect of the CDK4/6i, abemaciclib, and ET on the transcriptome of immune cell populations in 13 matched-pair advanced and metastatic estrogen receptor-positive/HER2- breast tumor biopsies. We tested the association of immune cell population gene signatures with survival in publicly available datasets. RESULTS: We profiled 170,798 cells from bone, breast, lymph node, and liver biopsies. We found that the expression of genes associated with interferon response are downregulated in many T-cell populations. The expression of genes associated with antigen presentation was upregulated in tumor-associated macrophages (TAM) and dendritic cells after treatment. The relative proportion of TREM2+ TAMs decreases after treatment with abemaciclib and ET in late progressors, and lower expression of the TREM2+ TAM signature is associated with improved overall survival (OS) in patients with breast cancer. CONCLUSIONS: Our data reveal heterogeneous lymphoid and myeloid subpopulations in advanced and metastatic breast tumors that are associated with late progression on abemaciclib and ET and OS in patients with breast cancer.