Abstract 5219: Taxanes induce interleukin 6 cytokine in women's cancer and stromal cells in vitro

Abstract Background: Taxane microtubule stabilizers, including paclitaxel (PTX), docetaxel (DTX) and nab-paclitaxel (Nab-PTX), are standard of care in the treatment of women’s cancer alone or in combination with other therapies. The effects of specific taxanes on cancer cells have been well studied such as disruption of cell division and inhibition of cellular trafficking, inducing cancer cell death; however, their effect on the tumor microenvironment is less understood. Cytokines released by cancer cells into the tumor microenvironment such as interleukin 6 (IL-6) can contribute to therapeutic resistance. Specifically, IL-6 binds to the IL-6 receptor (IL-6R) consisting of alpha and beta subunits, and activates the JAK/STAT signaling pathway, promoting chemoresistance. Taxane effects on tumor microenvironment, specifically tumor vasculature, have been less studied. We hypothesized that PTX, DTX, and Nab-PTX, including pericytes, and human dermal lymphatic endothelial cells (HDLECs), result in IL-6 secretion unique to each taxane, promoting chemoresistance. Methods: Primary human pericytes and HDLECs, 5 human women’s cancer cell lines, and 2 human breast epithelial cell lines were grown in vitro. The CCK-8 cell viability/cytotoxicity assay determined IC50 potency for the taxanes in primary human cells and cancer cells. Quantitative-PCR and cytokine arrays were used to evaluate IL-6 transcript levels and protein secretion, and flow cytometry to determine the abundance of IL-6 receptors at the cell surface. Results: DTX had the lowest IC50 values with a range of 0.3 - 2.1 nM, followed by PTX with 1.0 - 4.0 nM, and Nab-PTX with 2.9 - 64.5 nM after 72h treatment across 5 different cancer cell lines. DTX and PTX increased IL-6 transcript levels more than 2-fold following 24h treatment, p<0.05), whereas Nab-PTX showed a slight increase (p > 0.05). MDA-MB-231 cells had the highest basal IL-6 transcript levels compared to cancer and stromal cells. All cells tested expressed both IL-6R subunits at varying levels, suggesting taxane chemoresistance via IL-6R activation is possible in cancer cells and tumor associated cells. Primary human pericytes or HDLECs did not reach 50% survival following 24h treatment of 10 nM taxanes. DTX increased pericyte IL-6 transcript levels by two-fold following 24h treatment, p<0.05. Preliminary cytokine array data revealed IL-6 was increased in 10 nM DTX-treated pericytes following 24h treatment compared to DMSO (2-fold change). Summary: We show that DTX is the most potent taxane following 72h treatment. DTX also induces IL-6 production in both women’s cancer cell lines and stromal cells, potentially contributing to chemoresistance and cancer progression. All cells express varying levels of IL-6R subunits, suggesting that combining DTX treatment with IL-6 inhibitors may prevent DTX resistance in women’s cancer patients. Citation Format: Samantha S. Yee, Jacky Gomez-Villa, Sonia L. Hernandez. Taxanes induce interleukin 6 cytokine in women's cancer and stromal cells in vitro [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 5219.