Sakuishi, KaoriApetoh, LionelSullivan, Jenna M.Blazar, Bruce R.Kuchroo, VijayAnderson, Ana2011-10-192010Sakuishi, Kaori, Lionel Apetoh, Jenna M. Sullivan, Bruce R. Blazar, Vijay K. Kuchroo, and Ana C. Anderson. 2010. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. The Journal of Experimental Medicine 207(10): 2187-2194.0022-1007http://nrs.harvard.edu/urn-3:HUL.InstRepos:5265958The 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 repre- sent 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.en-USJournal Article2011-10-1910.1084/jem.20100643