Dual role of endothelial Myct1 in tumor angiogenesis and tumor immunity

Myct1 inhibition controls tumor angiogenesis, remodels tumor immunity, and improves immunotherapy outcomes in mouse tumor models. DeMyctifying the tumor microenvironment Anti-angiogenic treatments have so far delivered only modest success in patients with cancer, and the interactions between the tumor microenvironment and immunotherapies need to be better understood. Kabir et al. identified Myct1 as a critical factor for tumor growth and progression through dual effects on vascular development and tumor immunity. MYCT1 interacted with Zona Occludens 1 and regulated Rho GTPase-mediated actin cytoskeleton dynamics, and deficiency promoted antitumor T cell and macrophage phenotypes. The combination of Myct1 inhibition and immunotherapy led to tumor regression and long-term survival in tumor-bearing mice, suggesting that MYCT1 may be a promising target for antitumor therapy in the future. 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 Myct1, a direct target of ETV2, was nearly exclusively expressed in endothelial cells. In preclinical mouse tumor models, Myct1 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 (P < 0.05) correlation between MYCT1 expression, angiogenesis, and antitumor immunity in human cancers, as suggested by decreased FOXP3 expression and increased antitumor macrophages in patients with low MYCT1 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. Myct1-deficient endothelial cells facilitated trans-endothelial migration of cytotoxic T lymphocytes and polarization of M1 macrophages. Myct1 targeting combined with anti-PD1 treatment significantly (P < 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 Myct1 in controlling tumor angiogenesis and reprogramming tumor immunity. Myct1-targeted vascular control, in combination with immunotherapy, may become an exciting therapeutic strategy.

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