Exosomes Associated with Human Ovarian Tumors Harbor a Reversible Checkpoint of T-cell Responses

Abstract

Nano-sized membrane-encapsulated extracellular vesicles isolated from the ascites fluids of ovarian cancer patients are identified as exosomes based on their biophysical and compositional characteristics. We report here that T cells pulsed with these tumor-associated exosomes during TCR-dependent activation inhibit various activation endpoints including translocation of NFκB and NFAT into the nucleus, upregulation of CD69 and CD107a, production of cytokines and cell proliferation. Additionally, the activation of virus-specific CD8+ T cells that are stimulated with the cognate viral peptides presented in the context of class I MHC is also suppressed by the exosomes. The inhibition occurs without loss of cell viability, and coincidentally with the binding and internalization of these exosomes. This exosome-mediated inhibition of T cells was transient and reversible: T cells exposed to exosomes can be reactivated once exosomes are removed. We conclude that tumor-associated exosomes are immunosuppressive, and represent a therapeutic target blockade of which would enhance the antitumor response of quiescent tumor-associated T cells and prevent the functional arrest of adoptively transferred tumor-specific T cells or chimeric antigen receptor (CAR) T cells.

Tumor-Derived Extracellular Vesicles Impair CD171-Specific CD4+ CAR T Cell Efficacy

“…It has been reported that TEVs reprogram CD8 + T cells to become suppressor cells inhibiting proliferation of other T cells (40). TEVs also inhibit T cell proliferation and cytolytic activity in effector T cells and other effector immune cells such as natural killer cells, and promote regulatory T cell proliferation and formation of myeloid-derived suppressor cells through their immunosuppressive cargo (9,(40)(41)(42). Of note, cytotoxic activity of CD171-specific CAR T cells was independent of NTRK2 expression, which is a marker of aggressive neuroblastoma.…”

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

“…As the name suggests, internalization is performed by measuring the uptake of a protein/cell or other material into a specific cell. More recently, this feature has been utilized to determine exosome uptake into a cell .…”

Hypoxia-Induced Matrix Metalloproteinase-13 Expression in Exosomes from Nasopharyngeal Carcinoma Enhances Metastases

“…Exosomes are nano-sized (50–100 nm in diameter) membrane-bound vesicles released by a variety of cell types, especially abundantly by tumor cells 19 . Recent evidence has highlighted a role for hypoxic tumor cell-derived exosomes in promoting tumor progression 20 .…”