Abstract 3285: Targeting interactions between tumor-associated macrophages and tumor cells to enhance chemotherapy response in a resection model of triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is the most lethal breast cancer subtype and lacks targeted treatment options. While immune checkpoint blockade leads to significant benefits when combined with chemotherapy, recurrence, metastasis, and chemoresistance remain major challenges. The purpose of this study was to assess the ability of a colony-stimulating factor 1 receptor inhibitor (CSF-1Ri) and an anti-CD47 (aCD47) monoclonal antibody to remodel the tumor microenvironment (TME) in a murine resection model of TNBC, and the benefit of such priming when administered with chemotherapy. We focused on targeting tumor-associated macrophages (TAMs) as they are the most abundant immune cell in the TME and are associated with worse metastasis free survival (MFS) and overall survival (OS). Targeting TAMs, specifically M2-like TAMs, has been shown to delay recurrence and prolong MFS and OS. We also sought to block the CD47-SIRPα interaction between TNBC cells and TAMs, because TNBC cells have higher levels of CD47 expression compared to other breast cancer subtypes, and high rates of CD47 expression are associated with worse MFS and OS and higher cancer stemness. We selected pexidartinib (PLX) as CSF-1Ri given its translational potential (FDA approved) and gemcitabine (GEM) as chemotherapy, given its immunomodulatory effects. To recapitulate the clinical setting, we utilized a survival resection model, allowing us to administer neoadjuvant and adjuvant therapy, and track the development of metastases. BALB/c mice were injected with 100, 000 4T1 mammary carcinoma cells in the flank, and tumors established over the course of six days. Mice were then exposed to daily administrations of PLX (8 mg/kg), every other day administration of aCD47 (8 mg/kg) and weekly administrations of GEM (60 mg/kg). The primary tumor was resected on day thirteen and mice were then exposed to adjuvant therapy using the dosing regimen outlined previously. The TME of the resected tumors was characterized by flow cytometry, and MFS and OS were recorded over a ninety-day period. Both PLX+GEM and aCD47+GEM significantly reduced total TAMs (39% and 40% reduction, respectively). However, Only PLX+GEM significantly shifted the M1:M2 ratio towards the pro-inflammatory M1-like phenotype. Both combinations led to a significant prolongation of MFS and OS compared to GEM therapy alone. Triple therapy (PLX+GEM+aCD47) led to the most significant depletion of TAMs (62% reduction compared to vehicle), and a favorable M1:M2 shift, while reducing cancer stem cells and increasing dendritic cells. Triple therapy also had the greatest prolongation of MFS and OS (prolonged by 30% and 31% compared to GEM, respectively). Thus, the therapeutics investigated led to a remodeling of the TNBC TME towards a favorable phenotype, leading to enhanced chemotherapy efficacy and prolonged survival. Citation Format: Matthew Emilio Fernandez, Yasir Alshehry, Raneem R. Aldaqqa, Harry D. Bear, Douglas H. Sweet, Sandro R. da Rocha. Targeting interactions between tumor-associated macrophages and tumor cells to enhance chemotherapy response in a resection model of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3285.