Reprogramming Antitumor Immune Responses with microRNAs
Final rept. 30 Sep 2011-29 Sep 2013
WISTAR INST OF ANATOMY AND BIOLOGY PHILADELPHIA PA
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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 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.
- Anatomy and Physiology
- Medicine and Medical Research