A conserved intratumoral regulatory T cell signature identifies 4-1BB as a pan-cancer target.

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.

• Authors: Zachary T Freeman, Thomas R Nirschl, Daniel H Hovelson, Robert J Johnston, John J Engelhardt, Mark J Selby, Christina M Kochel, Ruth Y Lan, Jingyi Zhai, Ali Ghasemzadeh, Anuj Gupta, Alyza M Skaist, Sarah J Wheelan, Hui Jiang, Alexander T Pearson, Linda A Snyder, Alan J Korman, Scott A Tomlins, Srinivasan Yegnasubramanian, Charles G Drake
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 130 Issue 3 Pg. 1405-1416 (03 02 2020) ISSN: 1558-8238 [Electronic] United States
• PMID: 32015231 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 4-1BB Ligand
• Neoplasm Proteins
• TNFRSF9 protein, human
• Tnfsf9 protein, mouse
• Tumor Necrosis Factor Receptor Superfamily, Member 9

Topics

• 4-1BB Ligand (immunology)
• Animals
• CD8-Positive T-Lymphocytes (immunology, pathology)
• Genome-Wide Association Study
• Humans
• Lymphocyte Depletion
• Lymphocytes, Tumor-Infiltrating (immunology, pathology)
• Mice, Inbred BALB C
• Neoplasm Proteins (immunology)
• Neoplasms, Experimental (immunology, pathology, therapy)
• RNA-Seq
• T-Lymphocytes, Regulatory (immunology, pathology)
• Tumor Necrosis Factor Receptor Superfamily, Member 9 (immunology)