Selective tubulin-binding drugs induce pericyte phenotype switching and anti-cancer immunity

Abstract

Angiogenesis; Microtubule-binding drugs; Pericytes

Angiogénesis; Medicamentos que se unen a los microtúbulos; Pericitos

Angiogènesi; Medicaments que s'uneixen als microtúbuls; Pericits

The intratumoral immune milieu is crucial for the success of anti-cancer immunotherapy. We show here that stromal modulation by the tubulin-binding anti-cancer drugs combretastatin A4 (CA-4) and eribulin improved tumor perfusion and anti-tumor immunity. This was achieved by reverting highly proliferative, angiogenic pericytes into a quiescent, contractile state which durably normalized the vascular bed and reduced hypoxia in mouse models of pancreatic neuroendocrine cancer, breast cancer and melanoma. The crucial event in pericyte phenotype switching was RhoA kinase activation, which distinguished CA-4 and eribulin effects from other anti-mitotic drugs such as paclitaxel and vinorelbine. Importantly, eribulin pre-treatment sensitized tumors for adoptive T cell therapy or checkpoint inhibition resulting in effector cell infiltration and better survival outcomes in mice. In breast cancer patients, eribulin neoadjuvant treatment induced pericyte maturity and RhoA kinase activity indicating similar vessel remodeling effects as seen in mice. Moreover, a contractile pericyte signature was associated with overall better survival outcome in two independent breast cancer cohorts. This underscores the potential of re-purposing specific anti-cancer drugs to enable synergistic complementation with emerging immunotherapies.

This work was funded by grants from the National Health and Medical Research Council (NHMRC, APP1141847), Worldwide Cancer Research (21-0257), Cancer Australia (PO411), Cancer Council Western Australia (1168) to RG and Cancer Australia (2002303) to BH. PKD is funded by NHMRC Investigator grant 2026403. The Translational Research Institute receives support from the Australian government. We thank Eisai Inc. for their financial support of the SOLTI-1007 trial and extend our gratitude to the patients who participated in the study.