Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity

Kaori Sakuishi, Lionel Apetoh, Jenna M. Sullivan, Bruce R. Blazar, Vijay K. Kuchroo, Ana C. Anderson

Research output: Contribution to journalArticle

984 Scopus citations

Abstract

The immune response plays an important role in staving off cancer; however, mechanisms of immunosuppression hinder productive anti-tumor immunity. T cell dysfunction or exhaustion in tumor-bearing hosts is one such mechanism. PD-1 has been identified as a marker of exhausted T cells in chronic disease states, and blockade of PD-1-PD-1L interactions has been shown to partially restore T cell function. We have found that T cell immunoglobulin mucin (Tim) 3 is expressed on CD8+ tumor-infiltrating lymphocytes (TILs) in mice bearing solid tumors. All Tim-3+ TILs coexpress PD-1, and Tim-3+PD- 1+ TILs represent the predominant fraction of T cells infiltrating tumors. Tim-3+PD-1+ TILs exhibit the most severe exhausted phenotype as defined by failure to proliferate and produce IL-2, TNF, and IFN-γ. We further find that combined targeting of the Tim-3 and PD-1 pathways is more effective in controlling tumor growth than targeting either pathway alone.

Original languageEnglish (US)
Pages (from-to)2187-2194
Number of pages8
JournalJournal of Experimental Medicine
Volume207
Issue number10
DOIs
StatePublished - Sep 27 2010

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