2. Academic Validation
  3. Bis-indole-derived NR4A1 antagonists inhibit colon tumor and splenic growth and T-cell exhaustion

Bis-indole-derived NR4A1 antagonists inhibit colon tumor and splenic growth and T-cell exhaustion

  • Cancer Immunol Immunother. 2023 Dec;72(12):3985-3999. doi: 10.1007/s00262-023-03530-3.
Kumaravel Mohankumar 1,  Gus Wright # 2 3,  Subhashree Kumaravel # 4,  Rupesh Shrestha 5,  Lei Zhang 1,  Maen Abdelrahim 6,  Robert S Chapkin 5 7,  Stephen Safe 8
Affiliations

Affiliations

  • 1 Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, 77843, USA.
  • 2 Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, 77843, USA.
  • 3 TAMU Flow Cytometry Facility, Texas A&M University, College Station, TX, 77843, USA.
  • 4 Department of Medical Physiology, College of Medicine, Texas A&M University, College Station, TX, 77843, USA.
  • 5 Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, 77843, USA.
  • 6 Houston Methodist Cancer Center, Institute of Academic Medicine and Weill Cornell Medical College, Houston, TX, 77030, USA.
  • 7 Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA.
  • 8 Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, 77843, USA. [email protected].
  • # Contributed equally.
PMID: 37847301 DOI: 10.1007/s00262-023-03530-3
Abstract

There is evidence that the Orphan Nuclear Receptor 4A1 (NR4A1, Nur77) is overexpressed in exhausted CD8 + T cells and regulates PD-L1 in tumors. This study investigated the effects of potent bis-indole-derived NR4A1 antagonists on reversing T-cell exhaustion and downregulating PD-L1 in colon tumors/cells. NR4A1 antagonists inhibited colon tumor growth and downregulated expression of PD-L1 in mouse colon MC-38-derived tumors and cells. TILs from MC-38 cell-derived colon tumors and splenic lymphocytes exhibited high levels of the T-cell exhaustion markers including PD-1, 2B4, TIM3+ and TIGIT and similar results were observed in the spleen, and these were inhibited by NR4A1 antagonists. In addition, treatment with NR4A1 antagonists induced cytokine activation markers interferon γ, granzyme B and perforin mRNAs and decreased TOX, TOX2 and NFAT in TIL-derived CD8 + T cells. Thus, NR4A1 antagonists decrease NR4A1-dependent pro-oncogenic activity and PD-L1 expression in colon tumors and inhibit NR4A1-dependent T-cell exhaustion in TILs and spleen and represent a novel class of mechanism-based drugs that enhance immune surveillance in tumors.

Keywords

Antagonists; CRC; Exhaustion; Inhibition; NR4A1; T-cell.

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