Abstract 6401: HMGB1 release predicts chemotherapy combinatorial efficacy with TIM-3 blockade

Abstract

Abstract We have recently shown that TIM-3 blockade promotes response to paclitaxel chemotherapy in preclinical breast cancer models through its ability to suppress uptake of HMGB1-DNA complexes by dendritic cells. However, it remains unclear why paclitaxel is necessary for response to TIM-3 blockade. Here we demonstrate that the taxanes paclitaxel and docetaxel induce the loss of HMGB1 from breast cancer cells in vitro and in vivo. Interestingly, this does not occur through loss of cellular integrity, but rather through an active secretion process involving ADP-ribosylation of HMGB1 by PARP1. PARP1 was activated by docetaxel treatment, as measured by detection of its cleaved form in the cytoplasm, and HMGB1 release was prevented by the use of the PARP inhibitor niraparib. Both PARP1 activation and ADP-ribosylation of HMGB1 were dependent upon the activity of TLR4, a known receptor for paclitaxel, as demonstrated with CRISPR/Cas9-generated knockout cells and TLR4 inhibitors. However, TLR4 stimulation alone was insufficient to induce HMGB1 release. By understanding how taxanes promote the release of HMGB1 we may be able to develop biomarkers for the selection of patients most likely to respond to the combination of chemotherapy and immunotherapy with TIM-3 blocking antibodies. Citation Format: Alexis Onimus, Jessica Mandula, Paulo Rodriguez, Brian Ruffell. HMGB1 release predicts chemotherapy combinatorial efficacy with TIM-3 blockade. [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 6401.