PMID- 20819923
OWN - NLM
STAT- MEDLINE
DCOM- 20110110
LR  - 20220331
IS  - 1540-9538 (Electronic)
IS  - 0022-1007 (Print)
IS  - 0022-1007 (Linking)
VI  - 207
IP  - 10
DP  - 2010 Sep 27
TI  - Upregulation of Tim-3 and PD-1 expression is associated with tumor 
      antigen-specific CD8+ T cell dysfunction in melanoma patients.
PG  - 2175-86
LID - 10.1084/jem.20100637 [doi]
AB  - The paradoxical coexistence of spontaneous tumor antigen-specific immune 
      responses with progressive disease in cancer patients furthers the need to 
      dissect the molecular pathways involved in tumor-induced T cell dysfunction. In 
      patients with advanced melanoma, we have previously shown that the 
      cancer-germline antigen NY-ESO-1 stimulates spontaneous NY-ESO-1-specific CD8(+) 
      T cells that up-regulate PD-1 expression. We also observed that PD-1 regulates 
      NY-ESO-1-specific CD8(+) T cell expansion upon chronic antigen stimulation. In 
      the present study, we show that a fraction of PD-1(+) NY-ESO-1-specific CD8(+) T 
      cells in patients with advanced melanoma up-regulates Tim-3 expression and that 
      Tim-3(+)PD-1(+) NY-ESO-1-specific CD8(+) T cells are more dysfunctional than 
      Tim-3(-)PD-1(+) and Tim-3(-)PD-1(-) NY-ESO-1-specific CD8(+) T cells, producing 
      less IFN-gamma, TNF, and IL-2. Tim-3-Tim-3L blockade enhanced cytokine production by 
      NY-ESO-1-specific CD8(+) T cells upon short ex vivo stimulation with cognate 
      peptide, thus enhancing their functional capacity. In addition, Tim-3-Tim-3L 
      blockade enhanced cytokine production and proliferation of NY-ESO-1-specific 
      CD8(+) T cells upon prolonged antigen stimulation and acted in synergy with 
      PD-1-PD-L1 blockade. Collectively, our findings support the use of Tim-3-Tim-3L 
      blockade together with PD-1-PD-L1 blockade to reverse tumor-induced T cell 
      exhaustion/dysfunction in patients with advanced melanoma.
FAU - Fourcade, Julien
AU  - Fourcade J
AD  - Department of Medicine and Division of Hematology/Oncology, University of 
      Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA.
FAU - Sun, Zhaojun
AU  - Sun Z
FAU - Benallaoua, Mourad
AU  - Benallaoua M
FAU - Guillaume, Philippe
AU  - Guillaume P
FAU - Luescher, Immanuel F
AU  - Luescher IF
FAU - Sander, Cindy
AU  - Sander C
FAU - Kirkwood, John M
AU  - Kirkwood JM
FAU - Kuchroo, Vijay
AU  - Kuchroo V
FAU - Zarour, Hassane M
AU  - Zarour HM
LA  - eng
GR  - UL1 TR000005/TR/NCATS NIH HHS/United States
GR  - R01 CA090360/CA/NCI NIH HHS/United States
GR  - R01CA112198/CA/NCI NIH HHS/United States
GR  - R01 CA157467/CA/NCI NIH HHS/United States
GR  - R01CA90360/CA/NCI NIH HHS/United States
GR  - R01 CA112198/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100906
PL  - United States
TA  - J Exp Med
JT  - The Journal of experimental medicine
JID - 2985109R
RN  - 0 (Antigens, CD)
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (CTAG1B protein, human)
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (HAVCR2 protein, human)
RN  - 0 (Hepatitis A Virus Cellular Receptor 2)
RN  - 0 (Interleukin-2)
RN  - 0 (Membrane Proteins)
RN  - 0 (PDCD1 protein, human)
RN  - 0 (Programmed Cell Death 1 Receptor)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Antigens, CD/biosynthesis/*immunology
MH  - Antigens, Neoplasm/immunology
MH  - Apoptosis Regulatory Proteins/biosynthesis/*immunology
MH  - CD8-Positive T-Lymphocytes/*immunology/metabolism/pathology
MH  - Epitopes, T-Lymphocyte/immunology
MH  - Hepatitis A Virus Cellular Receptor 2
MH  - Humans
MH  - Immunity, Cellular
MH  - Interferon-gamma/biosynthesis/immunology
MH  - Interleukin-2/biosynthesis/immunology
MH  - Melanoma/*immunology/pathology
MH  - Membrane Proteins/biosynthesis/*immunology
MH  - Programmed Cell Death 1 Receptor
MH  - Tumor Necrosis Factor-alpha/biosynthesis/immunology
MH  - Up-Regulation
PMC - PMC2947081
EDAT- 2010/09/08 06:00
MHDA- 2011/01/11 06:00
PMCR- 2011/03/27
CRDT- 2010/09/08 06:00
PHST- 2010/09/08 06:00 [entrez]
PHST- 2010/09/08 06:00 [pubmed]
PHST- 2011/01/11 06:00 [medline]
PHST- 2011/03/27 00:00 [pmc-release]
AID - jem.20100637 [pii]
AID - 20100637 [pii]
AID - 10.1084/jem.20100637 [doi]
PST - ppublish
SO  - J Exp Med. 2010 Sep 27;207(10):2175-86. doi: 10.1084/jem.20100637. Epub 2010 Sep 
      6.