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- Title
Bis-indole-derived NR4A1 antagonists inhibit colon tumor and splenic growth and T-cell exhaustion.
- Authors
Mohankumar, Kumaravel; Wright, Gus; Kumaravel, Subhashree; Shrestha, Rupesh; Zhang, Lei; Abdelrahim, Maen; Chapkin, Robert S.; Safe, Stephen
- 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.
- Subjects
T-cell exhaustion; COLON tumors; TUMOR growth; NUCLEAR receptors (Biochemistry); INDOLE; T cells; PERFORINS
- Publication
Cancer Immunology, Immunotherapy, 2023, Vol 72, Issue 12, p3985
- ISSN
0340-7004
- Publication type
Article
- DOI
10.1007/s00262-023-03530-3