Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response

Peng Jiang, Shengqing Gu, Deng Pan, Jingxin Fu, Avinash Sahu, Xihao Hu, Ziyi Li, Nicole Traugh, Xia Bu, Bo Li, Jun Liu, Gordon J. Freeman, Myles A. Brown, Kai W. Wucherpfennig, X. Shirley Liu

Research output: Contribution to journalArticle

105 Scopus citations

Abstract

Cancer treatment by immune checkpoint blockade (ICB) can bring long-lasting clinical benefits, but only a fraction of patients respond to treatment. To predict ICB response, we developed TIDE, a computational method to model two primary mechanisms of tumor immune evasion: the induction of T cell dysfunction in tumors with high infiltration of cytotoxic T lymphocytes (CTL) and the prevention of T cell infiltration in tumors with low CTL level. We identified signatures of T cell dysfunction from large tumor cohorts by testing how the expression of each gene in tumors interacts with the CTL infiltration level to influence patient survival. We also modeled factors that exclude T cell infiltration into tumors using expression signatures from immunosuppressive cells. Using this framework and pre-treatment RNA-Seq or NanoString tumor expression profiles, TIDE predicted the outcome of melanoma patients treated with first-line anti-PD1 or anti-CTLA4 more accurately than other biomarkers such as PD-L1 level and mutation load. TIDE also revealed new candidate ICB resistance regulators, such as SERPINB9, demonstrating utility for immunotherapy research.

Original languageEnglish (US)
Pages (from-to)1550-1558
Number of pages9
JournalNature Medicine
Volume24
Issue number10
DOIs
StatePublished - Oct 1 2018

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Jiang, P., Gu, S., Pan, D., Fu, J., Sahu, A., Hu, X., Li, Z., Traugh, N., Bu, X., Li, B., Liu, J., Freeman, G. J., Brown, M. A., Wucherpfennig, K. W., & Liu, X. S. (2018). Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nature Medicine, 24(10), 1550-1558. https://doi.org/10.1038/s41591-018-0136-1