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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1405-1416
Number of pages12
JournalJournal of Clinical Investigation
Volume130
Issue number3
DOIs
StatePublished - Mar 2 2020

ASJC Scopus subject areas

  • Medicine(all)

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    Freeman, Z. T., Nirschl, T. R., Hovelson, D. H., Johnston, R. J., Engelhardt, J. J., Selby, M. J., Kochel, C. M., Lan, R. Y., Zhai, J., Ghasemzadeh, A., Gupta, A., Skaist, A. M., Wheelan, S. J., Jiang, H., Pearson, A. T., Snyder, L. A., Korman, A. J., Tomlins, S. A., Yegnasubramanian, S., & Drake, C. G. (2020). A conserved intratumoral regulatory T cell signature identifies 4-1BB as a pan-cancer target. Journal of Clinical Investigation, 130(3), 1405-1416. https://doi.org/10.1172/JCI128672