Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 207, Issue 10, Pages 2187-2194Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20100643
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Funding
- National Institutes of Health [AI73748, NS038037, NS045937, NS030843, NS054096, CA72669, HL56067, AI056299]
- National Multiple Sclerosis Society
- Juvenile Diabetes Research Foundation Center for Immunological Tolerance at Harvard
- European Molecular Biology Organization
- Ragon Institute of the Massachusetts Institute of Technology
- Massachussetts General Hospital and Harvard
- Sankyo Foundation of Life Science
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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-gamma. 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.
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