Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
An impaired anti-tumor immunity is found in patients with cancer and represents a major obstacle in the successful development of different forms of immunotherapy. Several pathways have been described to explain the induction of T cell anergy in tumors; however, the translation of this understanding into new adjuvants for immunotherapy has been limited. Pharmacological inhibition of Notch-homolog-related proteins (Notch) in T cells leads to a similar inhibitory effect to that found in tumors. Thus, we aimed to determine the role of Notch in the function of T cells and to test the effect of the transgenic expression of Notch 1 intracellular active domain (N1IC) in a tumor model of T cell-based immunotherapy. Our results show an increased expression of Notch 1 and 2, but not Notch 3 and 4, in activated CD4+ and CD8+ T cells. In addition, conditional deletion of both Notch 1 and 2 in antigen-specific CD4+ and CD8+ T cells, but not individual deletion of Notch forms, prevented cell proliferation and IFNγ production. Interestingly, tumor-associated myeloid-derived suppressor cells (MDSC) inhibited the expression of Notch 1/2 in activated T cells at the same ratios at which they blocked T cell proliferation and IFNγ production. To address the relevance of the decreased expression of Notch in T cells in tumor-induced tolerance, we adoptively transferred antigen-specific CD8+ T cells over-expressing N1IC (OT-1 N1ICf/f Gnz-Cre+/-) or floxed controls, into mice bearing established 3LL tumors carrying the model antigen ovalbumin (OVA). A higher anti-tumor effect and IFNγ production was observed in tumor-bearing mice transferred with N1IC CD8+ cells, as compared to those receiving floxed cells. Then, we tested whether N1IC directly promoted T cell cytotoxicity. An increased antigen-specific killing against OVA-loaded cells was induced by N1IC CD8+ cells in vitro and in vivo, as compared to control cells. This effect correlated with an increased expression in N1IC CD8+ T cells of the degranulation marker CD107a and the effector molecules granzyme B and IFNγ. Interestingly, N1IC endogenously bound to granzyme B promoter, suggesting a direct role of N1IC in the induction of effector genes in T cells. Moreover, an increased expression of T cell survival receptors CD122, IL-7R, and CD44 was found in N1IC mice, suggesting a potential role of Notch signaling in T cell survival/stemness. Altogether, these results suggest the role of Notch-1/2 in T cell function and the potential use of N1IC as an adjuvant for T cell-based immunotherapy. Continuation of this work could enable the design of new therapeutic approaches to reverse T cell anergy in individuals with cancer.