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J Exp Med. 2015 Nov 16;212(12):2095-113. doi: 10.1084/jem.20150304. Epub 2015 Nov 2.

Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance.

Author information

1
National Cancer Institute, Bethesda, MD 20892 palmerd@mail.nih.gov restifo@nih.gov.
2
National Cancer Institute, Bethesda, MD 20892.
3
National Institute of Allergy and Infectious Disease, Bethesda, MD 20892.
4
National Cancer Institute, Bethesda, MD 20892 Medical Scientist Training Program, The Ohio State University College of Medicine, Columbus, OH 43210.
5
Sidra Medical and Research Center, Doha, Qatar.

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.

Comment in

PMID:
26527801
PMCID:
PMC4647263
DOI:
10.1084/jem.20150304
[Indexed for MEDLINE]
Free PMC Article

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