Tuberous sclerosis 1 promotes invariant NKT cell anergy and inhibits invariant NKT cell-mediated antitumor immunity.
Development of effective immune therapies for cancer patients requires better understanding of hurdles that prevent the generation of effective antitumor immune responses. Administration of α-galactosylceramide (α-GalCer) in animals enhances antitumor immunity via activation of the invariant NKT (iNKT) cells. However, repeated injections of α-GalCer result in long-term unresponsiveness or anergy of iNKT cells, severely limiting its efficacy in tumor eradication. The mechanisms leading to iNKT cell anergy remain poorly understood. We report in this study that the tuberous sclerosis 1 (TSC1), a negative regulator of mTOR signaling, plays a crucial role in iNKT cell anergy. Deficiency of TSC1 in iNKT cells results in resistance to α-GalCer-induced anergy, manifested by increased expansion of and cytokine production by iNKT cells in response to secondary Ag stimulation. It is correlated with impaired upregulation of programmed death-1, Egr2, and Grail. Moreover, TSC1-deficient iNKT cells display enhanced antitumor immunity in a melanoma lung metastasis model. Our data suggest targeting TSC1/2 as a strategy for boosting antitumor immune therapy.
Duke Scholars
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Related Subject Headings
- Ubiquitin-Protein Ligases
- Tumor Suppressor Proteins
- Tuberous Sclerosis Complex 2 Protein
- Tuberous Sclerosis
- Reverse Transcriptase Polymerase Chain Reaction
- Programmed Cell Death 1 Receptor
- Natural Killer T-Cells
- Mice, Knockout
- Mice, Inbred C57BL
- Mice
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Ubiquitin-Protein Ligases
- Tumor Suppressor Proteins
- Tuberous Sclerosis Complex 2 Protein
- Tuberous Sclerosis
- Reverse Transcriptase Polymerase Chain Reaction
- Programmed Cell Death 1 Receptor
- Natural Killer T-Cells
- Mice, Knockout
- Mice, Inbred C57BL
- Mice