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

Douglas C. Palmer, Geoffrey C. Guittard, Zulmarie Franco, Joseph G. Crompton, Robert L. Eil, Shashank J. Patel, Yun Ji, Nicholas J. 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

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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.

Original languageEnglish
Pages (from-to)2095-2113
Number of pages19
JournalJournal of Experimental Medicine
Volume212
Issue number12
DOIs
Publication statusPublished - 2015

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Palmer, D. C., Guittard, G. C., Franco, Z., Crompton, J. G., Eil, R. L., Patel, S. J., Ji, Y., Van Panhuys, N. J., Klebanoff, C. A., Sukumar, M., Clever, D., Chichura, A., Roychoudhuri, R., Varma, R., Wang, E., Gattinoni, L., Marincola, F. M., Balagopalan, L., Samelson, L. E., & Restifo, N. P. (2015). Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance. Journal of Experimental Medicine, 212(12), 2095-2113. https://doi.org/10.1084/jem.20150304