Tracking Cancer Immunotherapy: Dendritic Cell-Derived Exosomes

Dendritic cells (DCs) are essential in order to combat invading viruses and trigger antiviral responses. New immunotherapy techniques to fight cancer are based on a DC’s ability to capture foreign antigens and innately present them to specific cytotoxic T cells.

Dendritic cells (DCs) are essential in order to combat invading viruses and trigger antiviral responses. New immunotherapy techniques to fight cancer are based on a DC's ability to capture foreign antigens and innately present them to specific cytotoxic T cells. This kind of adaptive immunity is an evolutionary conserved pathway, one that has directly contributed to the selection of antigens and receptors each signaling vital antimicrobial protection. DCs are derived from bone marrow precursors and are widely recognized as the key antigen-presenting cell, critical for the induction of an immune response [1].

The use of exosomes derived from mature DCs (mDex) has been an important advancement in this field, following the fundamental discovery that Dex can induce a greater T cell stimulation when compared with immature DCs [2,3]. Research published this month in The Journal of Immunology reports that Dex appears to be an efficient means of CD8+ T cell activation, which also appears to coincide with Dex interacting with DCs (Fig. 1).

FIGURE 1. Dex interacts immune cells. In vivo studies show that Dex can (A) directly activate T cells when directly presented with peptide-MHC complexes, (B) indirectly activate T cells via either "cross-dressing" of APCs or by the uptake of exosomes and subsequent processing of the MHC APCs. (C) Dex can also promote activation of NK cells through NK-expressed IL-15Ra and NKG2D receptors.

  The team showed that dendritic cells use exosomes (packets of DNA, RNA, microRNA, and proteins sealed in vesicles) transfer MHC class I and II molecules between dendritic cells. In addition to indirect stimulation, they showed that Dex is a potent co-stimulatory molecule of CD86, which appears to help reprogram helper T cells. Furthermore, with a sophisticated APC-homing in addition to immunotherapy properties, Dex is being developed for use as a cell-free cancer vaccine in clinical settings [4]. New research shows cancer cells use exosome transport as a way to disrupt a DC's ability to signal and command the T cells required for an adaptive immune response. With the immune system compromised, a cancer cell is essentially free to re-program other cells to assist in their growth, survival, and metastases through micro-vesicle trafficking [5].

“This fundamental discovery sparked great interest in exploring the clinical application of Dex as immunotherapy by our group,” the report said. “Dendritic cells express a plethora of pathogen recognition receptors, such as toll-like receptors, scavenger receptors, and lectin receptors, which recognize evolutionarily conserved pathogen-associated molecular patterns, which contribute to an organism’s antimicrobial defense.”

The group has completed two phase I clinical trials, each autologous Dex loaded with MAGE tumor Ags [6]. In the first study, nine patients with non-small cell lung cancer received four weekly doses of Dex. Three of those patients showed an increase in systemic immunity, although only a minimal increase in Ag-specific T cell activity was detected. By the end of the trial study, progression of the disease had stabilized in some of the patients. The second clinical study used Dex loaded with MAGE3+ (also administered four times weekly) for advanced melanoma patients. Results from their study showed an objective response in one patient with a minor response, two stabilizations of disease, and one who continued to be stable 24 months while continuing Dex injections [7,8]. These important findings confirm the safety of Dex when administered to patients and pave the way for future clinical tests, while also highlighting the feasibility of commercial-scale, clinical Dex production. In review of this research, it appears that exosomes, Dex in particular, will continue to make key contributions to future immunotherapies and in the emerging field of cancer vaccines.   SOURCES [1,6] Pitt M, Charrier M, Viaud S, Chaput N, Zitvogel L. Dendritic Cell-Derived Exosomes as Immunotherapies in the Fight against Cancer. The Journal of Immunology. August, 2014; 193:1006-1011; doi; 10.4049/jimmunol.1400703. [2] Utsugi-Kobukai, S., H. Fujimaki, C. Hotta, M. Nakazawa, and M. Minami. 2003. MHC class I-mediated exogenous antigen presentation by exosomes secreted from immature and mature bone marrow derived dendritic cells. Immunol. Lett. 89: 125 131. [3] Utsugi-Kobukai, S., H. Fujimaki, C. Hotta, M. Nakazawa, and M. Minami. 2003. MHC class I-mediated exogenous antigen presentation by exosomes secreted from immature and mature bone marrow derived dendritic cells. Immunol. Lett. 89: 125 131. [4,5] Zitvogel, L., A. Regnault, A. Lozier, J. Wolfers, C. Flament, D. Tenza, P. Ricciardi- Castagnoli, G. Raposo, and S. Amigorena. 1998. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat. Med. 4: 594600. [7] Escudier, B., T. Dorval, N. Chaput, F. Andre, M. P. Caby, S. Novault, C. Flament, C. Leboulaire, C. Borg, S. Amigorena, et al. 2005. Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of the first phase I clinical trial. J. Transl. Med. 3: 10. [8] Morse, M. A., J. Garst, T. Osada, S. Khan, A. Hobeika, T. M. Clay, N. Valente, R. Shreeniwas, M. A. Sutton, A. Delcayre, et al. 2005. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer.J. Transl. Med. 3: 9.