Dual role of endothelial <i>Myct1</i> in tumor angiogenesis and tumor immunity

Abstract

The cross-talk between angiogenesis and immunity within the tumor microenvironment (TME) is critical for tumor prognosis. While pro-angiogenic and immunosuppressive TME promote tumor growth, anti-angiogenic and immune stimulatory TME inhibit tumor progression. Therefore, there is a great interest in achieving vascular normalization to improve drug delivery and enhance antitumor immunity. However, anti-vascular endothelial growth factor (VEGF) mechanisms to normalize tumor vessels have offered limited therapeutic efficacies for patients with cancer. Here, we report that <i>Myct1</i>, a direct target of ETV2, was nearly exclusively expressed in endothelial cells. In preclinical mouse tumor models, <i>Myct1</i> deficiency reduced angiogenesis, enhanced high endothelial venule formation, and promoted antitumor immunity, leading to restricted tumor progression. Analysis of The Cancer Genome Atlas (TCGA) datasets revealed a significant (<i>P</i> < 0.05) correlation between <i>MYCT1</i> expression, angiogenesis, and antitumor immunity in human cancers, as suggested by decreased <i>FOXP3</i> expression and increased antitumor macrophages in patients with low <i>MYCT1</i> expression. Mechanistically, MYCT1 interacted with tight junction protein Zona Occludens 1 and regulated Rho GTPase-mediated actin cytoskeleton dynamics, thereby promoting endothelial motility in the angiogenic environment. <i>Myct1</i>-deficient endothelial cells facilitated trans-endothelial migration of cytotoxic T lymphocytes and polarization of M1 macrophages. <i>Myct1</i> targeting combined with anti-PD1 treatment significantly (<i>P</i> < 0.05) increased complete tumor regression and long-term survival in anti-PD1-responsive and -refractory tumor models in mice. Our data collectively support a critical role for <i>Myct1</i> in controlling tumor angiogenesis and reprogramming tumor immunity. <i>Myct1</i>-targeted vascular control, in combination with immunotherapy, may become an exciting therapeutic strategy.