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A conserved intratumoral regulatory T cell signature identifies 4-1BB as a pan-cancer target
- Source :
- Journal of Clinical Investigation. March, 2020, Vol. 130 Issue 3, p1405, 12 p.
- Publication Year :
- 2020
-
Abstract
- Despite advancements in targeting the immune checkpoints program cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) for cancer immunotherapy, a large number of patients and cancer types remain unresponsive. Current immunotherapies focus on modulating an antitumor immune response by directly or indirectly expanding antitumor CD8 T cells. A complementary strategy might involve inhibition of Tregs that otherwise suppress antitumor immune responses. Here, we sought to identify functional immune molecules preferentially expressed on tumor-infiltrating Tregs. Using genome-wide RNA-Seq analysis of purified Tregs sorted from multiple human cancer types, we identified a conserved Treg immune checkpoint signature. Using immunocompetent murine tumor models, we found that antibody-mediated depletion of 4-1BB-expressing cells (4-1BB is also known as TNFRSF9 or CD137) decreased tumor growth without negatively affecting CD8 T cell function. Furthermore, we found that the immune checkpoint 4-1BB had a high selectivity for human tumor Tregs and was associated with worse survival outcomes in patients with multiple tumor types. Thus, antibody-mediated depletion of 4-1BB-expressing Tregs represents a strategy with potential activity across cancer types.<br />Introduction Immune checkpoint molecules are a group of surface proteins expressed on various immune cell subsets that can function as either stimulatory or inhibitory mediators, depending upon cell-specific and contextual [...]
- Subjects :
- Thermo Fisher Scientific Inc.
Janssen Inc.
Cancer treatment -- Analysis
Ipilimumab -- Analysis
Apoptosis -- Analysis
Cancer -- Analysis
RNA sequencing -- Analysis
Immunotherapy -- Analysis
Antibodies -- Analysis
Pharmaceutical industry -- Analysis
Immune response -- Analysis
Genomics -- Analysis
Scientific equipment industry -- Analysis
T cells -- Analysis
Biochemistry
Lymphocytes
Tumors
Cell death
Genomes
RNA
Health care industry
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 130
- Issue :
- 3
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.618128138
- Full Text :
- https://doi.org/10.1172/JCI128672