title: Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance.
abstract: Improving the functional avidity of effector T cells is critical in overcoming inhibitory factors within the tumor microenvironment and eliciting tumor regression. We have found that Cish, a member of the suppressor of cytokine signaling (SOCS) family, is induced by TCR stimulation in CD8(+) T cells and inhibits their functional avidity against tumors. Genetic deletion of Cish in CD8(+) T cells enhances their expansion, functional avidity, and cytokine polyfunctionality, resulting in pronounced and durable regression of established tumors. Although Cish is commonly thought to block STAT5 activation, we found that the primary molecular basis of Cish suppression is through inhibition of TCR signaling. Cish physically interacts with the TCR intermediate PLC-γ1, targeting it for proteasomal degradation after TCR stimulation. These findings establish a novel targetable interaction that regulates the functional avidity of tumor-specific CD8(+) T cells and can be manipulated to improve adoptive cancer immunotherapy.
authors.affiliation: National Cancer Institute, Bethesda, MD 20892 palmerd@mail.nih.gov restifo@nih.gov.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Palmer
authors.affiliation: National Cancer Institute, Bethesda, MD 20892.
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Guittard
authors.affiliation: National Cancer Institute, Bethesda, MD 20892.
authors.forename: Zulmarie
authors.initials: Z
authors.lastname: Franco
authors.affiliation: National Cancer Institute, Bethesda, MD 20892.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Crompton
authors.affiliation: National Cancer Institute, Bethesda, MD 20892.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Eil
authors.affiliation: National Cancer Institute, Bethesda, MD 20892.
authors.forename: Shashank J
authors.initials: SJ
authors.lastname: Patel
authors.affiliation: National Cancer Institute, Bethesda, MD 20892.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ji
authors.affiliation: National Institute of Allergy and Infectious Disease, Bethesda, MD 20892.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Van Panhuys
authors.affiliation: National Cancer Institute, Bethesda, MD 20892.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Klebanoff
authors.affiliation: National Cancer Institute, Bethesda, MD 20892.
authors.forename: Madhusudhanan
authors.initials: M
authors.lastname: Sukumar
authors.affiliation: National Cancer Institute, Bethesda, MD 20892 Medical Scientist Training Program, The Ohio State University College of Medicine, Columbus, OH 43210.
authors.forename: David
authors.initials: D
authors.lastname: Clever
authors.affiliation: National Cancer Institute, Bethesda, MD 20892.
authors.forename: Anna
authors.initials: A
authors.lastname: Chichura
authors.affiliation: National Cancer Institute, Bethesda, MD 20892.
authors.forename: Rahul
authors.initials: R
authors.lastname: Roychoudhuri
authors.affiliation: National Institute of Allergy and Infectious Disease, Bethesda, MD 20892.
authors.forename: Rajat
authors.initials: R
authors.lastname: Varma
authors.affiliation: Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.affiliation: National Cancer Institute, Bethesda, MD 20892.
authors.forename: Luca
authors.initials: L
authors.lastname: Gattinoni
authors.affiliation: Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.affiliation: National Cancer Institute, Bethesda, MD 20892.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Balagopalan
authors.affiliation: National Cancer Institute, Bethesda, MD 20892.
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Samelson
authors.affiliation: National Cancer Institute, Bethesda, MD 20892 palmerd@mail.nih.gov restifo@nih.gov.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D015151:Immunoblotting; D016219:Immunotherapy, Adoptive / Q000379:methods; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D020411:Oligonucleotide Array Sequence Analysis; D051966:Phospholipase C gamma / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D059467:Transcriptome / Q000235:genetics / Q000276:immunology; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology
chemical_list: D051966:Phospholipase C gamma; D011948:Receptors, Antigen, T-Cell; D050826:Suppressor of Cytokine Signaling Proteins