Published in
Rockefeller University Press, Journal of Experimental Medicine, 12(212), p. 2095-2113, 2015
DOI: 10.1084/jem.20150304
BMJ Publishing Group, Journal for ImmunoTherapy of Cancer, S2(3), 2015
DOI: 10.1186/2051-1426-3-s2-p39
Links
- ORCID
- ORCID
- Rockefeller University Press | PDF
- BMJ Publishing Group | PDF
- ORCID
- [www.immunotherapyofcancer.org] | PDF
- [europepmc.org] | PDF
- [europepmc.org] | PDF
- [www.researchgate.net] | PDF
- [www.ncbi.nlm.nih.gov] | PDF
- [jitc.biomedcentral.com] | PDF
- [www.ncbi.nlm.nih.gov] | PDF
Tools
Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance
,
Joseph G. Crompton,
Zulmarie Franco,
Nicholas Van Panhuys ,
Shashank J. Patel,
Robert L. Eil,
Yun Ji,
Christopher A. Klebanoff,
Rajat Varma,
Madhusudhanan Sukumar,
Anna Chichura,
David Clever,
Ena Wang,
Rahul Roychoudhuri
and other authors.
Full text: Download
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.