Investigating the potential of histotripsy to reprogram the tumor microenvironment by altering tumor vasculature

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Presentation Time: 02:00 PM - 02:15 PM
Abstract ID: 4700 - B

Presenting Author:
Heineken Queen Daguplo , Graduate Student at Univ. of Michigan Med. Sch.

Abstract:

Tumor hypoxia is an element of the immunosuppressive tumor microenvironment (TME) that contributes to abnormal tumor vasculature and exacerbates therapeutic resistance by impeding immune cell infiltration. We are investigating the ability of Histotripsy (Ht), a recently FDA-approved ultrasound-mediated, non-ionizing tumor ablation therapy, to trigger systemic immune response by inducing local immunogenic cell death and promoting subsequent intratumoral CD8⁺ T cell recruitment and activation. Here we show that partial Ht transiently abrogates tumor hypoxia, dampens hypoxia-inducible factor (HIF) signaling, and promotes downstream immunomodulation. Further, we found that reduction of tumor hypoxia correlated with a remodeling of tumor architecture, including decreased tumor cell density, altered tumor blood vessel diameter/branching, and diminished endothelial expression of CXCR4. Gradual recovery of hypoxia one week post-Ht was associated with corresponding tumor regrowth and restoration of HIF signaling that favored the angiogenic CXCL12/CXCR4 axis. These findings suggest that vascular changes linked to reduced hypoxia may create a critical window for improved efficacy of chemotherapeutic agents post-Ht to maximize their therapeutic effects. The potential of Ht to turn immunologically “cold” tumors into “hot” tumors through vascular normalization may provide a means to overcome therapeutic limitations of chemotherapy and radiotherapy.