{"doi":"10.17615/0yzv-cg23","title":"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 B220þ/CD86þ-activated B cells and CD4þ 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. Significance: Immunostimulatory chemotherapy combined with pharmacologic inhibition of TAMs results in durable treatment responses elicited by Th cells and B cells in claudin-low TNBC models.","journal":"UNC Libraries","year":2024,"id":499661,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9448,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":621374,"name":"Igor Bado","orcid":"0000-0001-8855-4750","position":1,"is_corresponding":false},{"id":1348485,"name":"S Aguirre","orcid":null,"position":2,"is_corresponding":false},{"id":1347593,"name":"Jingzhou Hu","orcid":"0000-0003-4402-3370","position":3,"is_corresponding":false},{"id":530460,"name":"Zhi Liu","orcid":"0000-0001-9785-9150","position":4,"is_corresponding":false},{"id":704000,"name":"Liangyu Zhang","orcid":"0000-0002-2701-0773","position":5,"is_corresponding":false},{"id":1347594,"name":"Nicola J. Lee","orcid":"0000-0001-7766-6095","position":6,"is_corresponding":false},{"id":857874,"name":"Diego A. Pedroza","orcid":"0000-0002-7355-2952","position":7,"is_corresponding":false},{"id":1184124,"name":"Sharat Singh","orcid":"0000-0001-8707-4317","position":8,"is_corresponding":false},{"id":1347595,"name":"Yun Wan","orcid":"0000-0001-8128-5180","position":9,"is_corresponding":false},{"id":700846,"name":"Joseph T. Chang","orcid":"0009-0009-0944-3338","position":10,"is_corresponding":false},{"id":365946,"name":"Daniel P. Hollern","orcid":"0000-0003-0332-5516","position":11,"is_corresponding":false},{"id":1347596,"name":"Y Xu","orcid":"0009-0006-1100-2935","position":12,"is_corresponding":false},{"id":1347597,"name":"Yu Gao","orcid":"0000-0001-7845-801X","position":13,"is_corresponding":false},{"id":1348258,"name":"J.M Rosen","orcid":null,"position":14,"is_corresponding":false},{"id":1347973,"name":"C.M Perou","orcid":null,"position":15,"is_corresponding":false},{"id":1347598,"name":"Yi Shen","orcid":"0000-0002-3198-1927","position":16,"is_corresponding":false},{"id":1347599,"name":"Ning Zhao","orcid":"0000-0001-7242-3262","position":17,"is_corresponding":false},{"id":1347600,"name":"Sufen Chen","orcid":"0000-0001-8453-0225","position":18,"is_corresponding":false},{"id":327184,"name":"Xiang Zhang","orcid":"0000-0003-1003-9892","position":19,"is_corresponding":false},{"id":639393,"name":"Clark Hamor","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:09:53.188165Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}