title: Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity.
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.
authors.affiliation: Center for Neurological Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kaori
authors.initials: K
authors.lastname: Sakuishi
authors.forename: Lionel
authors.initials: L
authors.lastname: Apetoh
authors.forename: Jenna M
authors.initials: JM
authors.lastname: Sullivan
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.forename: Ana C
authors.initials: AC
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000276:immunology* / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D000072597:Hepatitis A Virus Cellular Receptor 2; D007108:Immune Tolerance / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D051379:Mice; D058990:Molecular Targeted Therapy; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor; D011991:Receptors, Virus / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
chemical_list: D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D007376:Interleukin-2; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011991:Receptors, Virus; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
references.citation: Nature. 2006 Feb 9;439(7077):682-7
references.pmid: 16382236
references.citation: J Exp Med. 2006 Oct 2;203(10):2281-92
references.pmid: 16954372
references.citation: Blood. 2008 Mar 15;111(6):3220-4
references.pmid: 18203952
references.citation: Nat Med. 2006 Oct;12(10):1198-202
references.pmid: 16917489
references.citation: J Virol. 2003 Apr;77(8):4911-27
references.pmid: 12663797
references.citation: Nat Med. 2002 Aug;8(8):793-800
references.pmid: 12091876
references.citation: Gastroenterology. 2009 Aug;137(2):682-90
references.pmid: 19394336
references.citation: J Immunol. 2010 May 1;184(9):4696-707
references.pmid: 20351188
references.citation: Nat Rev Immunol. 2006 Oct;6(10):715-27
references.pmid: 16977338
references.citation: J Exp Med. 2008 Nov 24;205(12):2763-79
references.pmid: 19001139
references.citation: Nat Immunol. 2009 Jan;10(1):29-37
references.pmid: 19043418
references.citation: Immunity. 2009 Aug 21;31(2):309-20
references.pmid: 19664943
references.citation: J Immunol. 2009 May 1;182(9):5240-9
references.pmid: 19380770
references.citation: Nat Immunol. 2005 Sep;6(9):873-9
references.pmid: 16116467
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):15016-21
references.pmid: 18809920
references.citation: J Virol. 2006 Apr;80(7):3532-40
references.pmid: 16537621
references.citation: J Immunol. 2003 Feb 1;170(3):1257-66
references.pmid: 12538684
references.citation: Blood. 2009 Aug 20;114(8):1537-44
references.pmid: 19423728
references.citation: J Virol. 2009 Sep;83(18):9122-30
references.pmid: 19587053
references.citation: J Virol. 2006 Nov;80(22):11398-403
references.pmid: 16956940
references.citation: Eur J Immunol. 2000 Dec;30(12):3598-603
references.pmid: 11169402
references.citation: Int J Cancer. 2006 Jul 15;119(2):317-27
references.pmid: 16482562
references.citation: J Exp Med. 1998 Dec 21;188(12):2205-13
references.pmid: 9858507
references.citation: Nature. 2006 Sep 21;443(7109):350-4
references.pmid: 16921384
references.citation: Blood. 2009 Aug 20;114(8):1528-36
references.pmid: 19420358
references.citation: Blood. 2009 Aug 20;114(8):1545-52
references.pmid: 19417208
references.citation: Cancer Res. 2006 Apr 1;66(7):3381-5
references.pmid: 16585157
references.citation: Annu Rev Immunol. 2004;22:329-60
references.pmid: 15032581
references.citation: J Clin Invest. 2007 May;117(5):1137-46
references.pmid: 17476343
references.citation: Nature. 2002 Jan 31;415(6871):536-41
references.pmid: 11823861
references.citation: Nat Immunol. 2001 Mar;2(3):261-8
references.pmid: 11224527