Investigation of the stress response to mechanical versus thermal non-ablative focused ultrasound therapy in three in vivo murine cancer models

Background/introduction Within the focal point of focused ultrasound (FUS), high pressure fluctuations cause shear stress on cells and tissues with energy dissipation leading to heating of the targeted tissue. The extent of the mechanical and thermal effects strongly depends on the ultrasound parameters and also potentially the acoustic properties of the tumor. High temperatures lead to coagulative necrosis with little immunogenic response as tumor antigens most likely denature during the ablation. As antigen presentation by activated dendritic cells (DCs) is necessary to activate T cells during an anti-tumor immune response, we hypothesize that non-ablative FUS treatment can be used to increase tumor immunogenicity by activating molecules that enhance intratumor dendritic cell (DC) infiltration and T cell activation. One of the first steps in this process is an activated stress response, including surface calreticulin (CRT), high mobility group protein B1 (HMGB1) release, ATP secretion and heat shock protein 70 (HSP70) surface expression and release. Using non-ablative FUS, antigen release can be stimulated by mechanical stress, thermal stress, or both. Here, we examine the stress response following non-ablative FUS treatment in three murine tumor models with varying consistencies and determine the causative agent (mechanical or thermal energy) of the stress.