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PROTAC-mediated NR4A1 degradation as a novel strategy for cancer immunotherapy

Lei Wang1, Yufeng Xiao2, Yuewan Luo1

  • 1Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.

The Journal of Experimental Medicine
|February 9, 2024
PubMed

Insights

A novel cancer therapy targets the tumor microenvironment by degrading NR4A1, a key molecule maintaining immune suppression. This approach, using a proteolysis-targeting chimera (PROTAC) called NR-V04, shows promise for enhancing anti-cancer immune responses.

Area of Science:

  • Immunology
  • Oncology
  • Pharmacology

Background:

  • Effective cancer therapy necessitates targeting both cancer cells and the tumor microenvironment (TME).
  • NR4A1 is identified as a crucial molecule involved in maintaining an immune-suppressive TME.
  • Targeting NR4A1 presents a potential strategy for cancer immunotherapy.

Purpose of the Study:

  • To establish NR4A1 as a viable target for cancer immunotherapy.
  • To develop and characterize a novel proteolysis-targeting chimera (PROTAC) against NR4A1, named NR-V04.
  • To evaluate the efficacy and mechanism of NR-V04 in preclinical cancer models.

Main Methods:

  • Development of NR-V04, a PROTAC designed for NR4A1 degradation.
  • In vitro assessment of NR-V04's degradation kinetics.
  • In vivo studies to evaluate NR-V04's efficacy, safety, and impact on the tumor immune microenvironment in established tumors.
  • Analysis of immune cell populations including tumor-infiltrating B cells, effector memory CD8+ T cells, and monocytic myeloid-derived suppressor cells.

Main Results:

  • NR-V04 demonstrated rapid in vitro NR4A1 degradation and sustained degradation in tumors.
  • The PROTAC exhibited an excellent safety profile.
  • NR-V04 effectively inhibited and frequently eradicated established tumors.
  • Mechanistically, NR-V04 modulated key immune cell populations within the TME, including increasing tumor-infiltrating B cells and effector memory CD8+ T cells, while decreasing monocytic myeloid-derived suppressor cells.

Conclusions:

  • NR4A1 is validated as a therapeutic target for cancer immunotherapy.
  • NR-V04, a novel PROTAC, effectively degrades NR4A1, leading to tumor inhibition and eradication.
  • NR-V04 enhances anti-cancer immune responses by modulating the TME, offering a promising new therapeutic strategy for various cancers, including melanoma.

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