# Myct1 control of the angioimmune interface

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $518,199

## Abstract

ABSTRACT
Endothelial cells (ECs) form an essential part of the vasculature and are strategically located between blood and
tissues, functioning as a fundamental barrier between the tissue and the immune system. As such, ECs can be
viewed as an essential and active component regulating immune responses. We propose that EC's angiogenic
vs. immune-modulatory function can be linked through the same genetic mechanism. We recently reported that
Myct1 (MYC target 1), encoding a plasma membrane protein, is a novel regulator of angiogenesis. Myct1
expression is mainly restricted to ECs and tumor ECs. Global and EC-specific (Cdh5-Cre; Myct1f/f) Myct1 KO
mice display decreased tumor angiogenesis and reduced tumor growth. Unexpectedly, defective tumor
angiogenesis leads to an anti-tumor immune microenvironment. Particularly, tumors from Myct1 KO mice contain
more CD8+ cytotoxic T lymphocytes (CTLs) than tumors from littermate control mice. While Myct1 deficient ECs
display defects in EC motility, they support more robust CD8+ T cell trans-endothelial migration (TEM).
Importantly, analysis of human cancers has also identified MYCT1 as a modulator of cancer patients' angiogenic
and immune outcomes. Inhibition of Myct1 through knockout, siRNA treatment, or blocking monoclonal
antibodies, in combination with anti-PD1 antibody, significantly improved complete tumor regression, suggesting
that the better control of cancer depends on reduced angiogenesis and enhanced recruitment of CD8+ CTLs.
We identified that Myct1 could control the outcome of angiogenesis vs. CTL recruitment to tumors through Rhoa
vs. Rac1 Rho GTPase pathways. Moreover, we identified ZO1, also known as tight junction protein 1, to
associate with MYCT1. Deeper mechanistic investigations on the Myct1-Rho GTPases and MYCT1-ZO1
interaction will help better understand how ECs control angiogenesis vs. immunity. As Myct1 function is
conserved between mice and humans, findings from the proposed studies have high translational potential and
can be applied to human anti-cancer therapies. The overall goal is to uncover novel molecular mechanisms and
functions of MYCT1 in ECs and anti-tumor immunity. Particularly, we will test the hypothesis that Myct1 can
modulate EC angiogenesis vs. immune regulatory outcome. Aim 1 determines how Myct1-Rho GTPase
regulates tumor angiogenesis vs. tumor immunity. Aim 2 investigates the functional significance of MYCT1-ZO
in EC permeability and vessel integrity. Aim 3 is to further assess the efficacy of anti-MYCT1 antibodies for
targeting MYCT1 in tumor angiogenesis and growth. By completing the proposed studies, we will gain a deeper
mechanistic understanding of how Myct1 regulates angiogenesis and the consequence of immune output played
by ECs. The outcome will significantly impact the basic EC biology and therapeutic modality for cancer treatment.

## Key facts

- **NIH application ID:** 10862666
- **Project number:** 5R01CA271714-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** KYUNGHEE CHOI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $518,199
- **Award type:** 5
- **Project period:** 2023-06-09 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862666

## Citation

> US National Institutes of Health, RePORTER application 10862666, Myct1 control of the angioimmune interface (5R01CA271714-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10862666. Licensed CC0.

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