| Popis: |
Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype that lacks targeted treatment options. While immune check point blockade leads to significant benefits in the treatment of TNBC when in combination with chemotherapy, recurrence, metastasis, and drug resistance still remain a major challenge. The purpose of this study was to assess the ability of a colony-stimulating factor 1 receptor inhibitor (CSF-1Ri) to shift the phenotype of the tumor microenvironment (TME) in a mouse model of TNBC, and the potential benefit of such tumor priming when the CSF-1Ri is administered in combination with chemotherapy. We focused on targeting tumor-associated macrophages (TAMs) as they are the most abundant immune infiltrate in the TNBC TME and are associated with worse overall survival and an increased chance of metastasis. Targeting TAMs, specifically alternatively activated, anti-inflammatory M2-like TAMs, has been shown to inhibit tumor progression and improve overall survival in several different tumor models. We have selected pexidartnib (PLX) as the CSF-1Ri of choice given its translational potential (FDA approved) and gemcitabine (GMT) as chemotherapy, given its ability to target myeloid derived suppressor cells. We employed a mammary carcinoma 4T1in BALB/c mice as the immunocompetent tumor model. Mice were injected with 100,000 4T1 cells in the 4th mammary fat pad, and tumors grew over the course of fifteen days to a tumor volume of 40 mm3. Mice were then exposed to daily administrations of PLX (8 mg/kg), and weekly administrations of GMT (60 mg/kg). Tumor volumes were recorded every other day. The TME was analyzed with flow cytometry 24h post last treatment to characterize immune infiltrates. Regarding total TAMs (CD45+CD11b+F4/80+), only the combination therapy (11.8% ± 2.1) could significantly decrease this population compared to vehicle control (22% ± 2). PLX (4.7% ± 0.8) is shown to shift the phenotype of the TNBC TME by significantly reducing M2-like TAMs (CD45+CD11b+F4/80+CD206+) compared to vehicle control (15.6% ± 0.4). Interestingly, GMT also promotes a decrease in M2-like TAMs (6.6% ± 0.9), which is further reduced in combination therapy (2.2% ± 0.6), which showed a significant decrease when compared to both vehicle and standalone GMT. Both standalone GMT (82.1 mm3 ± 13.7) and combination therapy (75.7 mm3 ± 10.7) significantly decreased tumor burden compared to vehicle control (153.3 mm3 ± 37.2) after a week of treatment. Furthermore, after five weeks of treatment, combination therapy (304.6 mm3 ± 51.5) had a significant effect on tumor burden compared to GMT (596.9 mm3 ± 122.8), indicating a correlation between tumor phenotype and therapeutic benefit. In conclusion, targeting TAMs in TNBC primes the tumor for combination with chemotherapy in TNBC. Citation Format: Matthew E. Fernandez, Cory B. Fines, Fatemah S. Subul, Sulaiman S. Alhudaithi, Harry D. Bear, Douglas H. Sweet, Sandro R. da Rocha. Macrophage-targeting immunotherapy for triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2328. |
