Abstract P1-02-25: New Murine Mammary Tumor Cell Lines for Syngeneic Studies Including Immunotherapy

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Abstract Breast cancer (BC) is the most common cancer diagnosis in women globally, accounting for more than 1 in 10 new cancer diagnoses. While BC has historically been a poor candidate for immune checkpoint blockade (ICB), recent studies in triple-negative BC (TNBC) have demonstrated anti-PD-1 treatment efficacy when employed in conjunction with chemotherapy1. APOBEC3 (A3) enzymes, such as A3A and A3B, catalyze cytosine-to-uracil deamination in single-stranded DNA, leading to signature single base substitution mutations (SBS2 and SBS13). A3 expression and mutagenesis have been associated with poor clinical outcomes, including drug resistance2,3. Murine models for studying ICB and mutagenesis by human A3A and A3B are underdeveloped. Here, we address this gap by generating two independent mammary tumor cell lines and studying responsiveness to ICB. Two novel mammary cancer cell lines, MM001 and MM008, were isolated from spontaneously arising tumors in C57BL/6 MMTV-Cre+;p53fl/+ mice. Each tumor line was passaged serially in the mammary fat pads of C57BL/6 (WT) mice to obtain conditioned cell lines MM001i and MM008i, which formed consistent and reproducible tumors. Tumor immune infiltrates were investigated by immunohistochemistry for CD45 (pan-immune marker), CD3 (pan-T cell), CD8 (cytotoxic T cells), B220 (B cells), Mac-1 or CD11b (macrophages), and PD-L1. Cells were also assessed via flow cytometry for surface expression and interferon inducibility of immune markers PD-L1, MHC-I component H2-Kb, and CD155. Reproducibly growing tumors for each of MM001i and MM008i were achieved, with 50% of the tumors reaching the endpoint of 1000 mm3 around day 18 and day 21, respectively. Interestingly, despite a shared ancestral genetic background, ICB treatment of WT mice injected with MM001i and MM008i revealed differential responses. MM001i was poorly responsive, whereas MM008i showed complete tumor regression following treatment with anti-PD-1. In contrast, both MM001i and MM008i responded rapidly to anti-CTLA-4. These differential responses were not explained by surface expression of PD-L1 and MHC-1 component H2-Kb, which appeared to be basally and inducibly (IFN-β or IFN-γ) expressed at similar levels. Experiments are ongoing to deduce the underlying molecular mechanism, test additional ICB therapies, and study the impact of A3 mutagenesis. Thus, two novel murine mammary breast cancer cell lines have been established to evaluate immunotherapies in fully immune-competent C57BL/6 mice. Selected References: 1) Schmid, P. et. al. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med, 382, 810-821 (2020). 2) Law, E. K. et al. The DNA cytosine deaminase APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer. Sci Adv, 2, e1601737 (2016). 3) Gupta, A. et. al. APOBEC3 mutagenesis drives therapy resistance in breast cancer. bioRxiv, https://doi.org/10.1101/2024.04.29.591453 (2024). Citation Format: Thomas Kalantzakos, Anusha Soni, Cameron Durfee, Chris Mullally, Benjamin Troness, Reuben S. Harris, Harshita B. Gupta. New Murine Mammary Tumor Cell Lines for Syngeneic Studies Including Immunotherapy [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-02-25.

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