Endothelin Inhibition Potentiates Cancer Immunotherapy Revealing Mechanical Biomarkers Predictive of Response

Abstract

Abstract Immunotherapy efficacy depends on T cell trafficking to tumors and migrating to malignant cells to kill them. One barrier to T cell homing is the tumor blood vessel wall, which inhibits T cell attachment and transmigration through the endothelin B receptor, but antagonizing this receptor has not led to a clinically approved drug. One reason may be tumor hypo‐perfusion, which limits the area of perfused vessels for T cell attachment. If collapsed vessels can be decompressed and re‐perfused by alleviating tumor stiffness, then endothelin B receptor antagonism can improve immunotherapy. Here, it is tested whether the nonselective endothelin receptor blocker, bosentan, by simultaneously interfering with endothelin A receptor induced fibrosis, can normalize the tumor microenvironment thereby acting as a “mechanotherapeutic.” Tumor stiffness is monitored with ultrasound elastography and nanomechanical properties with atomic force microscopy to find an optimal dose, which reprograms cancer‐associated fibroblasts resulting in reduced collagen thereby decompressing vessels. Through this mechanism, T cell association with tumor vessels increases and immunosuppressive hypoxia is reduced. Additionally, bosentan increases the CD8 + T cells proliferating fraction. Ultrasound stiffness measurements correlate well with response to immunotherapy, suggesting the potential role of ultrasound elastography as a predictive biomarker of response to immune checkpoint inhibitors.