Single-cell evaluation reveals shifts in the tumor-immune niches that shape and maintain aggressive lesions in the breast

Abstract

There is an unmet clinical need for stratification of breast lesions as indolent or aggressive to tailor treatment. Here, single-cell transcriptomics and multiparametric imaging applied to a mouse model of breast cancer reveals that the aggressive tumor niche is characterized by an expanded basal-like population, specialization of tumor subpopulations, and mixed-lineage tumor cells potentially serving as a transition state between luminal and basal phenotypes. Despite vast tumor cell-intrinsic differences, aggressive and indolent tumor cells are functionally indistinguishable once isolated from their local niche, suggesting a role for non-tumor collaborators in determining aggressiveness. Aggressive lesions harbor fewer total but more suppressed-like T cells, and elevated tumor-promoting neutrophils and IL-17 signaling, disruption of which increase tumor latency and reduce the number of aggressive lesions. Our study provides insight into tumor-immune features distinguishing indolent from aggressive lesions, identifies heterogeneous populations comprising these lesions, and supports a role for IL-17 signaling in aggressive progression.

Single-Cell RNA Sequencing in Organ and Cell Transplantation

“…The scRNA-seq technique applied to transplanted breast cancer tumors in mice shows that the aggressive tumor niche is determined by a basal-like population and mixed-lineage cancer cells [195]. The analysis showed two luminal-like populations (i.e., major Luminal 1 and minor Luminal 2).…”

Understanding Drug Sensitivity and Tackling Resistance in Cancer

“…Profiling of tumor specimens at single-cell resolution has deepened our insight into the complexity of cancers. Analysis of spatial information using methods such as: multiplex immunofluorescence, spatial transcript profiling, multi-omic analysis with both chromatin accessibility and transcript profiling in the same cell, and imaging mass spectrometry has provided valuable insights about tumor heterogeneity (101)(102)(103)(104)(105). As such, recent work profiling residual disease specimens has highlighted a differential alveolar type 1 (AT1)/AT2 hybrid state of tumor cells that withstand active therapy in NSCLC and point to dynamic microenvironment changes (41).…”

Mapping Breast Cancer Microenvironment Through Single-Cell Omics

“…However, progressive tumor regions require increased proliferation and an immunosuppressive milieu. Immune-suppressive T cells secrete IL-17 to recruit neutrophils and macrophages ( 27 ), which play an important role in higher myeloid cell infiltration and tumor metastasis in the clinical patients.…”

“…Finally, bone marrow-derived suppressor cells (MDSCs), including polymorphonucler MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs), were identified in breast tumor patients and gradually infiltrate tumor site with disease progression ( 27 ). Similar to T cells, the heterogeneity of neutrophils and monocytes could still be seen in tumors and spleen.…”