Exosomes derived from tumor cells genetically modified to express Mycobacterium tuberculosis antigen: a novel vaccine for cancer therapy
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To examine the potential of exosomes derived from the tumor cells, which had been genetically modified to express a Mycobacterium tuberculosis antigen, as a cancer vaccine aimed at overcoming the weak immunogenicity of tumor antigens.
We transfected B16 melanoma cells with a plasmid encoding the M. tuberculosis antigen, early secretory antigenic target-6 (ESAT-6). The secreted exosomes bearing both tumor-associated antigens and the pathogenic antigen (or their epitopes) were collected. When the exosomes were injected into foot pads of mice, they significantly (p < 0.05) evoked cellular immunity against both ESAT-6, and B16 tumor cells. Intra-tumoral injection of the exosomes significantly suppressed (p < 0.001) tumor growth in syngeneic B16 tumor-bearing mice, while the exosomes derived from the non-transfected B16 cells showed no effect on tumor growth, although both exosomes should have similar tumor antigens.
Exosomes bearing both tumor antigens and the M. tuberculosis antigen (or their epitopes) have a high potential as a candidate for cancer vaccine to overcome the immune escape by tumor cells.
KeywordsCancer vaccine Early secretory antigenic target-6 (ESAT-6) Exogenous danger signal Exosomes Mycobacterium tuberculosis antigen Neoantigens Neoepitopes
Authors are grateful to Prof. Hideo Nariuchi for his kind and important advices. This work was supported by JSPS KAKENHI Grant Numbers 25350555 and 16K01394.
- Cohen CJ, Gartner JJ, Horovitz-Fried M, Shamalov K, Trebska-McGowan K, Bliskovsky VV, Parkhurst MR, Ankri C, Prickett TD, Crystal JS, Li YF, El-Gamil M, Rosenberg SA, Robbins PF (2015) Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes. J Clin Invest 125:3981–3991CrossRefPubMedPubMedCentralGoogle Scholar
- de Jonge MI, Pehau-Arnaudet G, Fretz MM, Romain F, Bottai D, Brodin P, Honoré N, Marchal G, Jiskoot W, England P, Cole ST, Brosch R (2007) ESAT-6 from Mycobacterium tuberculosis dissociates from its putative chaperone CFP-10 under acidic conditions and exhibits membrane-lysing activity. J Bacteriol 189:6028–6034CrossRefPubMedPubMedCentralGoogle Scholar
- Duan F, Duitama J, Al Seesi S, Ayres CM, Corcelli SA, Pawashe AP, Blanchard T, McMahon D, Sidney J, Sette A, Baker BM, Mandoiu II, Srivastava PK (2014) Genomic and bioinformatic profiling of mutational neoepitopes reveals new rules to predict anticancer immunogenicity. J Exp Med 211:2231–2248CrossRefPubMedPubMedCentralGoogle Scholar
- Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, Ivanova Y, Hundal J, Arthur CD, Krebber WJ, Mulder GE, Toebes M, Vesely MD, Lam SS, Korman AJ, Allison JP, Freeman GJ, Sharpe AH, Pearce EL, Schumacher TN, Aebersold R, Rammensee HG, Melief CJ, Mardis ER, Gillanders WE, Artyomov MN, Schreiber RD (2014) Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515:577–581CrossRefPubMedPubMedCentralGoogle Scholar
- Koyama Y, Sugiura K, Yoshihara C, Inaba T, Ito T (2015b) Highly effective non-viral antitumor gene therapy system comprised of biocompatible small plasmid complex particles consisting of pDNA, anionic polysaccharide, and fully deprotected linear polyethylenimine. Pharmaceutics 7:152–164CrossRefPubMedPubMedCentralGoogle Scholar
- Pathak SK, Basu S, Basu KK, Banerjee A, Pathak S, Bhattacharyya A, Kaisho T, Kundu M, Basu J (2007) Direct extracellular interaction between the early secreted antigen ESAT-6 of Mycobacterium tuberculosis and TLR2 inhibits TLR signaling in macrophages. Nat Immunol 8:610–618CrossRefPubMedGoogle Scholar
- Smith J, Manoranjan J, Pan M, Bohsali A, Xu J, Liu J, McDonald KL, Szyk A, LaRonde-LeBlanc N, Gao LY (2008) Evidence for pore formation in host cell membranes by ESX-1-secreted ESAT-6 and its role in Mycobacterium marinum escape from the vacuole. Infect Immun 76:5478–5487CrossRefPubMedPubMedCentralGoogle Scholar