Endothelin Inhibition Potentiates Cancer Immunotherapy Revealing Mechanical Biomarkers Predictive of Response

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.