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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Targeted Nanoparticles for Kidney Cancer Therapy

images[2]The objective of this proposal is to test targeted carbon nanotubes for their ability to thermally ablate kidney cancer. Carbon nanotubes (CNTs) are efficient transducers of near-infrared radiation (NIR) for laser-induced thermal therapy of kidney cancer in mouse models. Our goal is to improve the anti-tumor efficacy of CNTs by designing them to target cancer cells and surrounding endothelial cells following systemic administration. Specifically, we will develop carbon nanotubes that bind to uPAR, a surface receptor overexpressed in kidney cancers and supporting endothelium. We will use D5, a peptide designed in the laboratory, as the targeting ligand. In the past year, we developed a new chemical approach to conjugating the targeting peptide to nanotubes. We demonstrated that the peptide is cytotoxic to kidney cancer cells. We also showed that the combination of nanotubes and NIR is effective in inhibiting the clonogenic survival of cultured kidney cancer cells. Next year, we will assess the flow of nanotubes in the vasculature and their ability to accumulate and exert an anti-tumor effect in a mouse tumor model. This grant is a mentor/predoctoral award that also focuses on training of a predoctoral candidate. The predoctoral fellow carried out the experiments described in this progress report, attended the national AACR cancer meeting, presented his work in seminars, and was co-first author on an article on nanotubes as thermal ablation agents.
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Personal Author S. V. Torti