Research thoughts by:

Dennis Jones

Tumor-derived exosomes and T cell suppression

7/5/2022

Immunotherapy to stimulate a patient’s immune system to attack cancer cells has been shown to be effective in eliminating metastatic cancer cells, a leading cause of mortality in cancer patients. However, most breast cancers respond poorly to T cell-directed immunotherapies. We have evidence that exosomes secreted from breast cancer tumors can attenuate T cell activation. While numerous studies have documented the effect of cancer cell-derived exosomes on the cytotoxic activity of T cells, our preliminary data from our new mouse breast cancer model show that exosomes from mesenchymal cells recruited to breast tumors exert strong suppressive effects on T cell activation. We therefore hypothesize that exosomes from the breast tumor microenvironment represent an additional barrier for the efficacy of cancer immunotherapies. However, cancer associated mesenchymal cell (CA-MC) exosomes are poorly characterized. During the award period, we will utilize proteomic profiling to gain novel insights into how CA-MC exosomes mediate T cell suppression. We will also use CRISPR-Cas9 to delete candidate genes in CA-MCs and then test the ability of the edited CA-MC exosomes to inhibit T cell activation. These studies will allow us to better understand how CA-MCs inhibit T cells and will form the basis for developing new strategies to reverse local and systemic T cell suppression mediated by tumor-derived exosomes.