Dual role of endothelial Myct1 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 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.

High Endothelial Venules: A Vascular Perspective on Tertiary Lymphoid Structures in Cancer

“…In addition, a recent study has shown that genetic deletion of Myct1, a direct target gene of ETV2, was sufficient to normalize tumor vessels and induce TU-HEV formation in subcutaneous sarcoma, concomitant with antitumoral immunity. Myct1 deletion combined with immunotherapy was successful in increasing long-term survival in anti-PD1 refractory breast cancer model (120).…”

Nucleic Acid Sensing in the Tumor Vasculature

“…This has been attributed to a splicing variant involving exon 7 and has implications for anti-angiogenic cancer therapies [99]. Even recently, Myct1 was identified as a transcription factor in the tumor endothelium and was shown to play a dual role in tumor angiogenesis and tumor immunity [100]. In summary, these studies provide an overview of the emerging rationale and approaches for targeting RNA sensors to decrease angiogenesis, enhance vascular normalization, and improve the antitumor immune microenvironment.…”

Omics in urology: An overview on concepts, current status and future perspectives

“…In recent years, thanks to molecular biology, several therapeutic strategies in cancer diseases have been developed against neoangiogenesis. 70 Previous studies analysed the transcriptome of about thousands RCC patients, and highlighted the existence of seven distinct molecular renal cancer subgroups with different angiogenesis, immune, cell cycle, metabolism and stromal programs. The study of the different genetic mutations underlying neoangiogenesis was then applied to the various therapeutic approaches available today.…”