Chemotherapy Coupled to Macrophage Inhibition Induces T-cell and B-cell Infiltration and Durable Regression in Triple-Negative Breast Cancer
Abstract
Immunosuppressive elements within the tumor microenvironment, such as tumor-associated macrophages (TAM), can present a barrier to successful antitumor responses by cytolytic T cells. Here we employed preclinical syngeneic p53 null mouse models of triple-negative breast cancer (TNBC) to develop a treatment regimen that harnessed the immunostimulatory effects of low-dose cyclophosphamide coupled with the pharmacologic inhibition of TAMs using either a small-molecule CSF1R inhibitor or an anti-CSF1R antibody. This therapeutic combination was effective in treating several highly aggressive TNBC murine mammary tumor and lung metastasis models. Single-cell RNA sequencing characterized tumor-infiltrating lymphocytes including Th cells and antigen-presenting B cells that were highly enriched in responders to combination therapy. In one model that exhibited long-term posttreatment tumor regression, high-dimensional imaging techniques identified the close spatial localization of B220+/CD86+-activated B cells and CD4+ T cells in tertiary lymphoid structures that were present up to 6 weeks posttreatment. The transcriptional and metabolic heterogeneity of TAMs was also characterized in two closely related claudin-low/mesenchymal subtype tumor models with differential treatment responses. A murine TAM signature derived from the T12 model was highly conserved in human claudin-low breast cancers, and high expression of the TAM signature correlated with reduced overall survival in patients with breast cancer. This TAM signature may help identify human patients with claudin-low breast cancer that will benefit from the combination of cyclophosphamide and anti-CSF1R therapy. These studies illustrate the complexity of the tumor immune microenvironment and highlight different immune responses that result from rational immunotherapy combinations.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 20, 2022
- Source ID
- 10.1158/0008-5472.can-21-3714
Entities
People
- Charles M. Perou
- Clark Hamor
- Daniel Hollern
- Diego A Pedroza
- Igor Bado
- Jeffrey M. Rosen
- Jeffrey T. Chang
- Jingyuan Hu
- Licheng Zhang
- Na Zhao
- Nigel Lee
- Sergio Aguirre
- Shu-hsia Chen
- Swarnima Singh
- Xiang H-F Zhang
- Yang Gao
- Yichao Shen
- Ying‐Wooi Wan
- Yitian Xu
- Zhandong Liu
Organizations
- Baylor College of Medicine
- Cancer Prevention and Research Institute of Texas
- His Majesty's Railway Inspectorate
- National Cancer Institute
- National Institutes of Health
- The Breast Cancer Research Foundation
- United States Department of Defense
- University of North Carolina
- University of Texas Health Science Center at Houston