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Inhibition of Nr4a Receptors Enhances Antitumor Immunity by Breaking Treg-Mediated Immune Tolerance.
- Source :
-
Cancer research [Cancer Res] 2018 Jun 01; Vol. 78 (11), pp. 3027-3040. Date of Electronic Publication: 2018 Mar 20. - Publication Year :
- 2018
-
Abstract
- Enhanced infiltration of regulatory T cells (Treg) into tumor tissue is detrimental to patients with cancer and is closely associated with poor prognosis as they create an immunosuppressive state that suppresses antitumor immune responses. Therefore, breaking Treg-mediated immune tolerance is important when considering cancer immunotherapy. Here, we show that the Nr4a nuclear receptors, key transcription factors maintaining Treg genetic programs, contribute to Treg-mediated suppression of antitumor immunity in the tumor microenvironment. Mice lacking Nr4a1 and Nr4a2 genes specifically in Tregs showed resistance to tumor growth in transplantation models without exhibiting any severe systemic autoimmunity. The chemotherapeutic agent camptothecin and a common cyclooxygenase-2 inhibitor were found to inhibit transcriptional activity and induction of Nr4a factors, and they synergistically exerted antitumor effects. Genetic inactivation or pharmacologic inhibition of Nr4a factors unleashed effector activities of CD8 <superscript>+</superscript> cytotoxic T cells and evoked potent antitumor immune responses. These findings demonstrate that inactivation of Nr4a in Tregs breaks immune tolerance toward cancer, and pharmacologic modulation of Nr4a activity may be a novel cancer treatment strategy targeting the immunosuppressive tumor microenvironment. Significance: This study reveals the role of Nr4a transcription factors in Treg-mediated tolerance to antitumor immunity, with possible therapeutic implications for developing effective anticancer therapies. Cancer Res; 78(11); 3027-40. ©2018 AACR .<br /> (©2018 American Association for Cancer Research.)
- Subjects :
- Animals
Autoimmunity drug effects
CD8-Positive T-Lymphocytes drug effects
CD8-Positive T-Lymphocytes immunology
Cell Line, Tumor
Cyclooxygenase 2 metabolism
Cyclooxygenase 2 Inhibitors pharmacology
HEK293 Cells
Humans
Immune Tolerance drug effects
Immunotherapy methods
Mice
Mice, Inbred C57BL
T-Lymphocytes, Cytotoxic drug effects
T-Lymphocytes, Cytotoxic immunology
T-Lymphocytes, Regulatory drug effects
Transcription, Genetic drug effects
Transcription, Genetic immunology
Tumor Microenvironment drug effects
Tumor Microenvironment immunology
Autoimmunity immunology
Immune Tolerance immunology
Receptors, Cytoplasmic and Nuclear immunology
T-Lymphocytes, Regulatory immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 78
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 29559474
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-17-3102