Reprogramming Antitumor Immune Responses with microRNAs

images[11]During the tenure of this pilot project, we identified that miR-181a is universally up-regulated in ovarian cancer infiltrating lymphocytes. Unexpectedly, overexpression of miR-181a in anti-tumor (protective) T cells results in impaired effector functions in the tumor microenvironment, rather than in enhanced TCR recognition of tumor antigens. Genomic analysis of the genes silenced upon miR-181a up-regulation revealed a approximately 2-fold decrease in the expression of the enzyme Tryptophan 2,3-dioxygenase (TDO2), suggesting that impaired tryptophan metabolism may be the cause of defective responses by tumor- reactive T cells overexpressing miR-181a. No differences in immunological readouts were found between ovarian cancer-bearing hosts treated with cisplatin vs. oxiliplatin. Our results indicate that miR-181a impairs, rather than augmenting, T cell protection in ovarian cancer, and point to miR-181a as a novel target for down-regulating interventions. J. R. Conejo-Garcia
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