# Tumor-derived Exosome Induction of Dendritic Cell Tolerization

> **NIH NIH F32** · DUKE UNIVERSITY · 2020 · $64,926

## Abstract

Project Summary/Abstract
Dendritic cells (DCs) are professional antigen presenting cells that bridge innate and adaptive immunity via the
cross-presentation of antigens. DCs play an indispensable role in cancer immunity where they activate
cytotoxic T cells to clear tumor cells. Despite this, cancers have developed methods to inactivate DCs in order
to avoid immune clearance in a process called DC tolerization. In order to communicate with other cell types,
cancer cells utilize 30-150 nm nanovesicles called exosomes. Exosomes released from the tumor transit to
distant sites, including lymph nodes, where they promote the formation of a tumor supportive
microenvironment called the ‘pre-metastatic niche’ by delivering specific RNAs and proteins. Due to the ability
of exosomes to promote metastasis over long distances and the importance of DCs to tumor progression, it is
likely that exosomes play a role in DC tolerization. Our laboratory has demonstrated that a DC fatty acid
oxidation (FAO) metabolic program is a major determining factor in inducing tolerization. FAO-induced DC
tolerization is characterized by the promotion of immunosuppressive cell types like regulatory T cells (Tregs)
and by a reduced ability of DCs to present antigen. Preliminary data shows that tumor-derived exosomes are
significantly taken up by DCs, both locally and in distant lymph nodes, but the effects of these exosomes
remain unclear. We hypothesize that tumor-derived exosomes drive DC metabolism towards a FAO state
resulting in an immunotolerant phenotype and cancer progression. First, we will use melanoma cell lines
isolated from BRAFV600E and PTEN-/- transgenic mice that are engineered to express a CD63-RFP fusion
protein to fluorescently tag melanoma exosomes. In tumor implant models, the biodistribution of exosomes to
DCs and the resulting phenotypic changes of DCs in the lymph nodes, and primary tumor will be assessed
using flow cytometry and RNA-seq. Next, we will utilize cellular metabolism analysis and high-resolution mass
spectrometry to determine the impact of tumor-derived exosomes on changes in the flux of metabolites
through key metabolic pathways. We anticipate that melanoma exosomes cause increased FAO leading to
subsequent DC tolerization. Finally, the therapeutic application of utilizing oncolytic herpes viral vectors
(oHSV1) to both kill tumor cells and suppress FAO in dendritic cells will be investigated. oHSV1 will be used to
drive melanoma specific expression of either miR-33 or shRNA targeted to CPT1a preceded by a nucleotide
motif (x-motif) targeting these small RNAs to exosomes. Both these RNAs target CPT1a an important mediator
of FAO. Therefore, oHSV1 can be utilized to target DCs with mir33/shCPT1a containing exosomes, reduce
FAO and promote an anti-tumor immune response while simultaneously killing tumor cells. Ultimately, these
proposed studies will generate an improved understanding of the tumor-derived factors that drive dendritic
cells towar...

## Key facts

- **NIH application ID:** 10065970
- **Project number:** 1F32CA247067-01A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Michael Paul Plebanek
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $64,926
- **Award type:** 1
- **Project period:** 2020-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065970

## Citation

> US National Institutes of Health, RePORTER application 10065970, Tumor-derived Exosome Induction of Dendritic Cell Tolerization (1F32CA247067-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10065970. Licensed CC0.

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