Reprogramming Antitumor Immune Responses with microRNAs

Abstract : During the previous funding cycle we demonstrated that miR-181a is up-regulated in tumor-reactive T cells as they survive in the ovarian cancer microenvironment, and that miR-181a overexpressing anti-tumor T cells exert defective protection against malignant progression, compared to control anti-tumor lymphocytes. These effects are not the result of impaired memory differentiation, but are most likely caused by a functional defect in their effector activity, probably due to impaired Tryptophan (and, subsequently, glucose) metabolism. Correspondingly, downregulating, rather than augmenting, the expression of miR-181a in anti-tumor T cells, becomes a desirable goal for lymphocyte adoptive transfer protocols. Furthermore, we have demonstrated for the first time the feasibility of re-programming immune responses against established ovarian orthotropic tumors through intraperitoneal delivery of nanocomplexes carrying synthetic miRNAs. Our results provide a rationale for the modulation of miRNA activity in tumor leukocytes as a novel cancer intervention.