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

被引：144

作者：

Palmer, Douglas C. ^{[1
]}

Guittard, Geoffrey C. ^{[1
]}

Franco, Zulmarie ^{[1
]}

Crompton, Joseph G. ^{[1
]}

Eil, Robert L. ^{[1
]}

Patel, Shashank J. ^{[1
]}

Ji, Yun ^{[1
]}

Van Panhuys, Nicholas ^{[2
]}

Klebanoff, Christopher A. ^{[1
]}

Sukumar, Madhusudhanan ^{[1
]}

Clever, David ^{[1
,3
]}

Chichura, Anna ^{[1
]}

Roychoudhuri, Rahul ^{[1
]}

Varma, Rajat ^{[2
]}

Wang, Ena ^{[4
]}

Gattinoni, Luca ^{[1
]}

Marincola, Francesco M. ^{[4
]}

Balagopalan, Lakshmi ^{[1
]}

Samelson, Lawrence E. ^{[1
]}

Restifo, Nicholas P. ^{[1
]}

机构：

[1] NCI, Bethesda, MD 20892 USA

[2] NIAID, Bethesda, MD 20892 USA

[3] Ohio State Univ, Coll Med, Med Scientist Training Program, Columbus, OH 43210 USA

[4] Sidra Med & Res Ctr, Doha, Qatar

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2015年 / 212卷 / 12期

基金：

美国国家卫生研究院;

关键词：

BLOOD MONONUCLEAR-CELLS; ADOPTIVE IMMUNOTHERAPY; SH2; DOMAIN; SOCS BOX; SH2-CONTAINING PROTEIN; NEGATIVE REGULATION; VIRUS-INFECTION; IMMUNE CELLS; HIGH-AVIDITY; RECEPTOR;

D O I：

10.1084/jem.20150304

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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-gamma 1, 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.

引用

页码：2095 / 2113

页数：19

共 87 条

[1] Type I Cytokines Synergize with Oncogene Inhibition to Induce Tumor Growth Arrest [J].