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: Douglas C Palmer, Geoffrey C Guittard, Zulmarie Franco, Joseph G Crompton, Robert L Eil, Shashank J Patel, Yun Ji, Nicholas Van Panhuys, Christopher A Klebanoff, Madhusudhanan Sukumar, David Clever, Anna Chichura, Rahul Roychoudhuri, Rajat Varma, Ena Wang, Luca Gattinoni, Francesco M Marincola, Lakshmi Balagopalan, Lawrence E Samelson, Nicholas P Restifo
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 212 Issue 12 Pg. 2095-113 (Nov 16 2015) ISSN: 1540-9538 [Electronic] United States
• PMID: 26527801 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Receptors, Antigen, T-Cell
• Suppressor of Cytokine Signaling Proteins
• cytokine inducible SH2-containing protein
• Phospholipase C gamma

Topics

• Animals
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Cells, Cultured
• Humans
• Immune Tolerance (genetics, immunology)
• Immunoblotting
• Immunotherapy, Adoptive (methods)
• Melanoma, Experimental (genetics, immunology, therapy)
• Mice, 129 Strain
• Mice, Inbred C57BL
• Mice, Knockout
• Microscopy, Confocal
• Oligonucleotide Array Sequence Analysis
• Phospholipase C gamma (immunology, metabolism)
• Protein Binding (immunology)
• Receptors, Antigen, T-Cell (immunology)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (immunology)
• Suppressor of Cytokine Signaling Proteins (deficiency, genetics, immunology)
• Transcriptome (genetics, immunology)
• Tumor Microenvironment (genetics, immunology)