Exosomes from Dendritic Cells Loaded with Chaperone-Rich Cell Lysates Elicit a Potent T Cell Immune Response Against Intracranial Glioma in Mice

Abstract

Chaperone-rich cell lysates (CRCLs) may play an important role in the development of anti-tumor vaccines. Tumor-derived CRCLs have been reported to activate dendritic cells (DCs) to elicit potent anti-tumor activity. However, the role of DC-derived exosomes (DEXs) secreted from DCs loaded with CRCLs in the treatment of tumors has not been clearly determined. In the present study, DEXs were generated from DCs loaded with CRCLs derived from GL261 glioma cells. These DEXs, designated DEX (CRCL-GL261), were then used to treat DCs to create DEX (CRCL-GL261)-DCs. The DEX (CRCL-GL261)-DCs were found to promote cell proliferation and cytotoxic T lymphocyte (CTL) activity of CD4(+) and CD8(+) T cells in vitro compared with DEX (GL261)-DCs, which were loaded with DEXs derived from DCs loaded with GL261 tumor cell lysates. DEX (CRCL-GL261)-DCs significantly prolonged the survival of mice with tumors and inhibited tumor growth in vivo. In addition, DEX (CRCL-GL261)-DCs induced enhanced T cell infiltration in intracranial glioma tissues compared with other treatments. DEX (CRCL-GL261)-DCs induced strong production of anti-tumor cytokines, including interleukin-2 and interferon-γ. Moreover, depletion of CD4(+) and CD8(+) T cells significantly impaired the anti-tumor effect of DEX (CRCL-GL261)-DCs. Finally, DEX (CRCL-GL261)-DCs were found to negatively regulate Casitas B cell lineage lymphoma (Cbl)-b and c-Cbl signaling, leading to the activation of phosphatidyl inositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) signaling in T cells. In summary, we present evidence that DEX (CRCL-GL261)-DCs induce more potent and effective anti-tumor T cell immune responses and delineate the underlying mechanism by which DEX (CRCL-GL261)-DCs exerted their anti-tumor activity through modulating Cbl-b and c-Cbl signaling. These results provide novel and promising insight for the development of an anti-tumor vaccine.

The Origin and Functions of Exosomes in Cancer

“…It is found that exosomes released from glioma cells have the potency to act as antigen sources for immune system activation ( 99 ). Experiments conducted with dendritic exosomes revealed its anti-tumor activity by the induction of T-lymphocytes ( 100 ). Anti-cancer immunity of DC-derived exosomes has also proved in B16F10 melanoma model ( 101 ).…”

The Dichotomy of Tumor Exosomes (TEX) in Cancer Immunity: Is It All in the ConTEXt?

“…Curiously, CRCL has strong proteomic overlaps with exosomes, and has a novel structure that may lead to similar DC responses as TEX [ 81 ]. In a similar set of experiments, but using syngeneic DEX from CRCL-pulsed DCs in the same murine brain tumor model, those DEX drove CBL (Cbl proto-oncogene, E3 ubiquitin protein ligase) and CBLB (Cbl proto-oncogene B, E3 ubiquitin protein ligase) signaling with AKT (protein kinase B) and ERK (extracellular regulated kinase) signaling in stimulated T cells [ 82 ].…”

Engineered Tumor-Derived Extracellular Vesicles: Potentials in Cancer Immunotherapy

“…Moreover, tumor-derived chaperon rich cell lysates containing Hsp70, Hsp90, calreticulin, and glucose-regulated protein 94 have been reported to activate DCs (58). Bu et al (59) demonstrated that exosomes from DCs loaded with chaperone-rich cell lysates could elicit a potent T cell immune response against intracranial glioma in mice. These findings suggested that chaperons are potent candidates to increase the immunostimulatory effect of TEXs.…”