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J Exp Med. 2010 Sep 27;207(10):2187-94. doi: 10.1084/jem.20100643. Epub 2010 Sep 6.

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

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1
Center for Neurological Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

Erratum in

  • J Exp Med. 2011 Jun 6;208(6):1331.

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.

PMID:
20819927
PMCID:
PMC2947065
DOI:
10.1084/jem.20100643
[Indexed for MEDLINE]
Free PMC Article

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