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

Vidya C Sinha,Florencia Mcallister,Yuan Qi,Jiansu Shao,Helen Piwnica-Worms,Amanda L Rinkenbaugh,Dean Y Maeda,Xiaomei Zhang,John A Zebala,Sabrina Jeter-Jones,Mingchu Xu,Xinhui Zhou

doi:10.1038/s41467-021-25240-z

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.

Highlights

There is an unmet clinical need for stratification of breast lesions as indolent or aggressive to tailor treatment
Our work provides insight on the heterogeneous transcriptional and phenotypic populations that comprise these lesions, supports a role for IL-17 signaling in mammary lesion progression, and generates a collection of tumor and immune niche features that may be useful in identifying lesions that are capable of aggressive behavior, including those that might be otherwise considered indolent
We showed that indolent and aggressive lesions were comprised of distinct tumorimmune cell niches (Fig. 8)

Summary

Introduction

There is an unmet clinical need for stratification of breast lesions as indolent or aggressive to tailor treatment. 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. We interrogate the tumor and immune niche compartments of both indolent and aggressive lesions, and functionally measure the degree to which these features shape lesion behavior, using a combination of single-cell transcriptomic analyses, multiparametric imaging, and functional studies. Our work provides insight on the heterogeneous transcriptional and phenotypic populations that comprise these lesions, supports a role for IL-17 signaling in mammary lesion progression, and generates a collection of tumor and immune niche features that may be useful in identifying lesions that are capable of aggressive behavior, including those that might be otherwise considered indolent

Methods

Results

Conclusion