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Abstract
The Induction of Macrophage Endoplasmic Reticulum Stress by Irradiated-Tumor Derived Extracellular Vesicles Supports the Adoption of a Pro-Tumor Phenotype
Sitara Mahmoodi, Depts. of Biology and Chemistry, with Dr. Sarah Golding, Dept. of Biology
Recent studies have shown that long term exposure of tumor cells to sub-lethal levels of endoplasmic reticulum (ER) stress leads to the suppression of anti-tumor immunity through the manipulation of myeloid cells in the tumor microenvironment.1 While this effect seems to be dependent upon the ability of cancer cells to “transfer” the state of ER stress to myeloid cells, i.e. to initiate ER stress signaling in myeloid cells independent of the original stimulus, exactly how stressed cancer cells accomplish this is still not well understood1. Our focus is on exosomes which are extracellular vesicles and how they play a significant role in this mechanism. In recent studies, we demonstrated how extracellular vesicles secreted by irradiated melanoma cancer cells (IR-EVs) induce ER stress in Bone Marrow Dendritic Cells (BMDCs). In addition, BMDCs treated with IR-EVs demonstrated enhanced STAT3 and p38 signaling, two related pathways that have been demonstrated to induce tolerogenic DC phenotypes, in an ER stress dependent manner2. We have also found that IR- EVs stimulate the production of IL-10, a major negative regulator of antitumor immunity, from BMDCs and that this expression can be eliminated by STAT3 inhibition2. However, using a T-Cell Receptor/ tumor- associated antigen (TCR/TAA) system to model the interaction between BMDCs and cytotoxic T cells from a tumor rejection antigen (Pmel/gp100), we have observed that pharmaceutical ER stress or STAT3 inhibition dramatically inhibits T cell proliferation and IFN-gamma expression in response to antigen pulsed BMDCs. This suggests that ER stress and STAT3 signaling are both necessary for the presentation of tumor antigens to cytotoxic T cells, indicating that inhibition of these pathways would not be a desirable approach to enhance antitumor immunity in vivo. Thus, our current focus is on finding a way to inhibit the production or activity of these IR-EVs directly, inhibiting their effects on DCs in the body while leaving STAT3 signaling in proliferating T cells unaltered.
Publication Date
2020
Current Academic Year
Freshman
Faculty Advisor/Mentor
Sarah Golding, Ph.D.
Sponsorship
Virginia Commonwealth University. Undergraduate Research Opportunities Program
Is Part Of
VCU Undergraduate Research Posters
Rights
© The Author(s)