Editors' ChoiceCancer

Unsilencing antitumor T cell activity

Sci. Signal.  15 Dec 2015:
Vol. 8, Issue 407, pp. ec370
DOI: 10.1126/scisignal.aaf0596

Antigen-specific CD8+ T cells, also known as cytotoxic T cells (CTLs), exhibit antitumor activity; however, the inhibitory tumor microenvironment often leads to reduced T cell receptor (TCR) signaling and suppression of the immune response. Noting that suppressor of cytokine signaling (SOCS) proteins inhibit T cell responses, Palmer et al. investigated whether loss of the SOCS family member Cish in CD8+ T cells could enhance their antitumor activity. In response to TCR stimulation in vitro and in mice, wild-type CD8+ T cells produced increased amounts of Cish mRNA and protein compared with those in unstimulated cells. CD8+ T cells from Cish-deficient mice exhibited enhanced antigen sensitivity, increased proliferation, and increased production of proinflammatory cytokines, such as interferon-γ, compared with their wild-type counterparts. In a mouse model of melanoma, mice that received Cish-deficient transgenic CD8+ T cells with a TCR specific for a melanoma antigen exhibited decreased tumor burden and increased survival compared with mice that received Cish-sufficient transgenic CD8+ T cells. Microarray analysis revealed that compared with wild-type CD8+ T cells, Cish-deficient mouse CD8+ T cells had increased expression of genes encoding products that are required for cytotoxicity, suggesting that Cish inhibited TCR signaling. Western blotting analysis showed that the abundances of total and phosphorylated phospholipase c–γ1 (PLC-γ1), which mediates signaling downstream of the TCR, were increased in TCR-stimulated Cish-deficient CD8+ T cells compared with those in stimulated wild-type cells. As a result, Cish-deficient CD8+ T cells exhibited increased calcium signaling and enhanced activation of calcium-dependent transcription factors. In response to TCR stimulation, Cish coimmunoprecipitated with PLC-γ1, which was ubiquitylated and then degraded. Together, these data suggest that Cish inhibits signaling in TCR-stimulated CD8+ T cells, raising the possibility that therapeutically targeting Cish may enhance the antitumor activity of these cells.

D. C. Palmer, G. C. Guittard, Z. Franco, J. G. Crompton, R. L. Eil, S. J. Patel, Y. Ji, N. Van Panhuys, C. A. Klebanoff, M. Sukumar, D. Clever, A. Chichura, R. Roychoudhuri, R. Varma, E. Wang, L. Gattinoni, F. M. Marincola, L. Balagopalan, L. E. Samelson, N. P. Restifo, Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance. J. Exp. Med. 212, 2095–2113 (2015). [PubMed]