Modulating therapeutic antitumor T cell immunity with MicroRNAs (156.21)

Abstract

Abstract MicroRNAs are attractive candidates for enhancing the therapeutic effectiveness of adoptive T cell therapy, although overcoming tumor-induced immunosuppression in the tolerogenic ovarian cancer microenvironment remains a formidable barrier. We hypothesized that over-expression of miR181a in adoptively transferred tumor-reactive T cells would result in sustained anti-tumor immunity within the tolerogenic ovarian tumor microenvironment. To test this, congenic tumor-reactive T cells were intraperitoneally injected into mice bearing established transplantable ovarian tumors. Twelve and 26 days post-transfer, RNA was isolated from sorted peritoneal host or transferred CD4 and CD8 T cells. Contrary to our initial hypothesis, miR181a expression was significantly and exponentially greater in transferred CD4 and CD8 T cells, compared to host-derived T cells at these temporal points during which the function of transferred T cells was impeded by the tolerogenic microenvironment. This suggested an unexpected negative role for miR181a in the context of T cell immunotherapy. To confirm these findings, T cells over-expressing miR181a were adoptively transferred into tumor-bearing mice and survival was monitored. Compared to mice receiving either non-transduced or control-vector transduced T cells, mice treated with T cells over-expressing miR181a had significantly reduced survival, supporting the novel finding that miR181a may have a negative role in adoptive T cell immunotherapy.