Abstract
Abstract Targeting of tumors over-expressing HER2 using trastuzumab provides clinical benefit for patients by inhibiting HER2 signalling and enhancing immune responses against the tumor by antibody-dependent cell-mediated cytotoxicity (ADCC). Cytokines such as IL-7 augment cytotoxic anti-viral responses through up-regulation of FasL, whereas TLR1/2 agonists enhance T cell cytotoxic responses but may also promote tumor cell survival. We therefore investigated the ability of IL-7R or TLR1/2 agonism to enhance trastuzumab-mediated ADCC. We first determined the contribution of various human immune cell subsets (e.g. monocytes, T cells, NK cells) to deliver ADCC of human tumor cells using a live high-content imaging assay in both 2D and 3D formats. Our results demonstrate that trastuzumab evoked immune cell dependent, concentration-dependent killing of tumor cells that exhibited some differential sensitivity dependent upon the cell culture format. We then tested trastuzumab-mediated killing in the absence or presence of IL-7R or TLR1/2 agonism, and noted evident donor and immune cell dependent modulation of the cytotoxic response. Modulation of this cytotoxic response was associated with differential immune cell marker expression when analysed by flow cytometry. Our findings provide mechanistic insight into trastuzumab-mediated ADCC and highlight how cytokine receptor and TLR pathways may modulate this response. Citation Format: Mark Bryant, Gokhan Tut, Neale Harrison, Emma Welsh, Ines Morano, Arshpreet Kaur, Ashley Pegg, Hujo Chan, Zhi Li, Jamie Cowley, Catherine Brady, John Gordon, Nicholas Barnes, Omar Qureshi. Dependence of human immune cell type, and impact of IL-7R or TLR1/2 agonism, upon trastuzumab-mediated ADCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4045.
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