Gene related to anergy in lymphocytes deficiency confers spontaneous tumor regression (TUM2P.897)

Abstract

Abstract T cell tolerance is the main obstacle to successful cancer immunotherapy; thus, today it is a high priority to develop strategies to break T cell tolerance and thereafter enhance T-cell cytotoxicity towards tumor cells. We, as well as other groups, have acknowledged the E3 ubiquitin ligase, Gene related to anergy in lymphocytes (Grail), as an essential component of T-cell tolerance phenotype. Here we report that Grail expression is highly upregulated in CD8+ T cells infiltrated into the EG-7 tumors compared to T cells in lymphoid tissues, and Grail deficiency confers spontaneous protection against inoculated EG-7 tumors. Importantly, therapeutic transfer of naïve tumor-antigen-specific Grail deficient CD8+ T cells into the wild-type hosts was sufficient to reject established tumors. Mechanistically, Grail deficient CD8+ T cells exhibit augmented effector cytokine expression and enhanced cytolytic function compared to wild-type CD8+ T cells, and are resistant to the suppression mediated by regulatory T cells. Moreover, the elevated cytotoxic function of Grail-deficient CD8+ T cells essentially depends on TCR and IL-21-signaling pathway; Grail promotes IL21R ubiquitination and degradation. Altogether, our data demonstrate that Grail is a crucial factor that controls anti-tumor activity of cytotoxic T cells, thus, inhibition of Grail may be a beneficial immunotherapeutic approach to induce potent immune responses against established tumors.