Editors' ChoiceCancer Immunology

Tumor-mediated suppression of T cells is EZ(H2)

Sci. Signal.  12 Jan 2016:
Vol. 9, Issue 410, pp. ec7
DOI: 10.1126/scisignal.aaf2209

Increased numbers of tumor-infiltrating lymphocytes (TILs) in tumors correlate with better survival of cancer patients. Furthermore, TILs that produce multiple proinflammatory cytokines or effector molecules mount an enhanced antitumor immune response (see commentary by Bantug and Hess). However, the consumption of glucose by tumor cells prevents TILs from becoming fully activated. Zhao et al. investigated the effect of tumor cells on the abundance in T cells of the methyltransferase EZH2, a component of the Polycomb transcriptional repressor complex. Immunohistochemical analysis showed that EZH2+ TILs from human ovarian cancers produced multiple effector cytokines compared with their EZH2 counterparts and were more resistant to spontaneous and chemotherapy-induced apoptosis. Activation of T cells in vitro concomitantly stimulated the synthesis of EZH2 and the production of the intracellular domain of Notch (NICD), the signaling of which is required for T cell function and survival. EZH2 inhibited the expression of genes encoding repressors of Notch signaling, and the expression of Notch target genes in activated T cells was reduced by knockdown or inhibition of EZH2. T cells cultured in ovarian cancer cell medium exhibited decreased glycolysis, reduced production of multiple cytokines, and increased apoptosis, responses that were improved by the addition of glucose. Culturing T cells in cancer cell medium maintained their expression of microRNAs that targeted EZH2. Adoptive transfer experiments indicated that melanoma metastasis was greater in mice that received tumor-specific T cells in which EZH2 was knocked down or inhibited than in mice that received untreated T cells. Last, analysis of ovarian cancer patient tumors showed that the percentage of EZH2+CD8+ T cells predicted outcome and long-term survival. Together, these data suggest that glucose deprivation by tumor cells results in a decrease in the abundance of EZH2 in T cells, which results in defective effector cytokine production and increased apoptosis.

E. Zhao, T. Maj, I. Kryczek, W. Li, K. Wu, L. Zhao, S. Wei, J. Crespo, S. Wan, L. Vatan, W. Szeliga, I. Shao, Y. Wang, Y. Liu, S. Varambally, A. M. Chinnaiyan, T. H. Welling, V. Marquez, J. Kotarski, H. Wang, Z. Wang, Y. Zhang, R. Liu, G. Wang, W. Zou, Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat. Immunol. 17, 95–103 (2016). [PubMed]

G. R. Bantug, C. Hess, Glycolysis and EZH2 boost T cell weaponry against tumors. Nat. Immunol. 17, 41–42 (2016). [PubMed]