TY - JOUR
T1 - Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance
AU - Palmer, Douglas C.
AU - Guittard, Geoffrey C.
AU - Franco, Zulmarie
AU - Crompton, Joseph G.
AU - Eil, Robert L.
AU - Patel, Shashank J.
AU - Ji, Yun
AU - Van Panhuys, Nicholas
AU - Klebanoff, Christopher A.
AU - Sukumar, Madhusudhanan
AU - Clever, David
AU - Chichura, Anna
AU - Roychoudhuri, Rahul
AU - Varma, Rajat
AU - Wang, Ena
AU - Gattinoni, Luca
AU - Marincola, Francesco M.
AU - Balagopalan, Lakshmi
AU - Samelson, Lawrence E.
AU - Restifo, Nicholas P.
PY - 2015/11/16
Y1 - 2015/11/16
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84948654905&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84948654905&partnerID=8YFLogxK
U2 - 10.1084/jem.20150304
DO - 10.1084/jem.20150304
M3 - Article
C2 - 26527801
AN - SCOPUS:84948654905
SN - 0022-1007
VL - 212
SP - 2095
EP - 2113
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 12
ER -