Department of Critical Care Medicine, Department of Clinical Pharmacy, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610000, China
West China School of Pharmacy, Sichuan University, Chengdu 610000, China
§ Mengran Guo, Xing Duan, and Xingchen Peng contributed equally to this work.
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A lipid-based latent membrane protein 2 (LMP2)-messenger RNA (mRNA) vaccine was developed to treat nasopharyngeal carcinoma. After internalization into dendritic cells (DCs), the LMP2 antigen can be expressed and presented to the surface of DCs by forming peptide-major histocompatibility complex (pMHC) complexes. Then, the T cells recognized the complexes, differentiated, and proliferated into antigen-specific T cells. Finally, the antigen-specific T cells attacked the tumor cells that expressed LMP2 epitopes.
Abstract
Nasopharyngeal carcinoma (NPC) is a serious and highly invasive epithelial malignancy that is closely associated with Epstein‒Barr virus (EBV). Due to the lack of therapeutic vaccines for NPC, we selected EBV latent membrane protein 2 (LMP2) as a preferable targeting antigen to develop a lipid-based LMP2-mRNA (mLMP2) vaccine. Full-length mLMP2 expressing LMP2 was first synthesized using an invitro transcription method and then encapsulated into (2,3-dioleacyl propyl) trimethylammonium chloride (DOTAP)-based cationic liposomes to obtain the mRNA vaccine (LPX-mLMP2). The cell assays showed that the antigen-presenting cells were capable of highly efficient uptake of LPX-mLMP2 and expression of LMP2. LMP2 could subsequently be presented to form the peptide-major histocompatibility complex (pMHC). Furthermore, LPX-mLMP2 could accumulate in the spleen, express antigens, promote the maturation of dendritic cells and stimulate antigen-specific T-cell responses invivo. It dramatically inhibited the tumor growth of the LMP2-expressing tumor model after three doses of vaccination. Additionally, the proliferation of antigen-specific T cells in the tumor site made a good sign for the promise of mRNA vaccines in virus-induced cancer. Overall, we provided a newly developed antigen-encoding mRNA vaccine with advantages against NPC. We also demonstrated that mRNA vaccines are attractive candidates for cancer immunotherapy.
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References
[1]
Sung, H.; Ferlay, J.; Siegel, R. L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin.2021, 71, 209–249.
Tyagi, R. K.; Parmar, R.; Patel, N. A generic RNA pulsed DC based approach for developing therapeutic intervention against nasopharyngeal carcinoma. Hum. Vaccin. Immunother.2017, 13, 854–866.
Coghill, A. E.; Hildesheim, A. Epstein–Barr virus antibodies and the risk of associated malignancies: Review of the literature. Am. J. Epidemiol.2014, 180, 687–695.
Zhu, Q. Y.; Kong, X. W.; Sun, C.; Xie, S. H.; Hildesheim, A.; Cao, S. M.; Zeng, M. S. Association between antibody responses to Epstein–Barr virus glycoproteins, neutralization of infectivity, and the risk of nasopharyngeal carcinoma. mSphere2020, 5, e00901–20.
Zeng, Y.; Si, Y. F.; Lan, G. P.; Wang, Z.; Zhou, L.; Tang, M. Z.; Sj, O. B.; Lan, J.; Zhou, X. Y.; Wang, Y. L. et al. LMP2-DC vaccine elicits specific EBV-LMP2 response to effectively improve immunotherapy in patients with nasopharyngeal cancer. Biomed. Environ. Sci.2020, 33, 849–856.
Ge, Y. Y.; Zhou, Z. X.; Wang, X. L.; Zhou, Y. B.; Liu, W.; Teng, Z. P.; Zeng, Y. Invitro evaluation of the therapeutic effectiveness of EBV-LMP2 recombinant adenovirus vaccine in nasopharyngeal carcinoma. Biomed. Pharmacother. 2020, 121, 109626.
[9]
Taylor, G. S.; Jia, H.; Harrington, K.; Lee, L. W.; Turner, J.; Ladell, K.; Price, D. A.; Tanday, M.; Matthews, J.; Roberts, C. et al. A recombinant modified Vaccinia Ankara vaccine encoding Epstein–Barr virus (EBV) target antigens: A phase I trial in UK patients with EBV-positive cancer. Clin. Cancer Res.2014, 20, 5009–5022.
Feng, C.; Li, Y. J.; Ferdows, B. E.; Patel, D. N.; Ouyang, J.; Tang, Z. M.; Kong, N.; Chen, E. G.; Tao, W. Emerging vaccine nanotechnology: From defense against infection to sniping cancer. Acta Pharm. Sin. B2022, 12, 2206–2223.
Thompson, M. G.; Burgess, J. L.; Naleway, A. L.; Tyner, H.; Yoon, S. K.; Meece, J.; Olsho, L. E. W.; Caban-Martinez, A. J.; Fowlkes, A. L.; Lutrick, K. et al. Prevention and attenuation of COVID-19 with the BNT162b2 and mRNA-1273 vaccines. N. Engl. J. Med.2021, 385, 320–329.
Islam, M. A.; Rice, J.; Reesor, E.; Zope, H.; Tao, W.; Lim, M.; Ding, J. X.; Chen, Y. H.; Aduluso, D.; Zetter, B. R. et al. Adjuvant-pulsed mRNA vaccine nanoparticle for immunoprophylactic and therapeutic tumor suppression in mice. Biomaterials2021, 266, 120431.
Kong, N.; Zhang, R. N.; Wu, G. W.; Sui, X. B.; Wang, J. Q.; Kim, N. Y.; Blake, S.; De, D.; Xie, T.; Cao, Y. H. et al. Intravesical delivery of KDM6A-mRNA via mucoadhesive nanoparticles inhibits the metastasis of bladder cancer. Proc. Natl. Acad. Sci. USA2022, 119, e2112696119.
Lin, Y. X.; Wang, Y.; Ding, J. X.; Jiang, A. P.; Wang, J.; Yu, M.; Blake, S.; Liu, S. S.; Bieberich, C. J.; Farokhzad, O. C. et al. Reactivation of the tumor suppressor PTEN by mRNA nanoparticles enhances antitumor immunity in preclinical models. Sci. Transl. Med.2021, 13, eaba9772.
Uchida, S.; Kinoh, H.; Ishii, T.; Matsui, A.; Tockary, T. A.; Takeda, K. M.; Uchida, H.; Osada, K.; Itaka, K.; Kataoka, K. Systemic delivery of messenger RNA for the treatment of pancreatic cancer using polyplex nanomicelles with a cholesterol moiety. Biomaterials2016, 82, 221–228.
Kranz, L. M.; Diken, M.; Haas, H.; Kreiter, S.; Loquai, C.; Reuter, K. C.; Meng, M.; Fritz, D.; Vascotto, F.; Hefesha, H. et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature2016, 534, 396–401.
Vik-Mo, E. O.; Nyakas, M.; Mikkelsen, B. V.; Moe, M. C.; Due-Tonnesen, P.; Suso, E. M. I.; Sæbøe-Larssen, S.; Sandberg, C.; Brinchmann, J. E.; Helseth, E. et al. Therapeutic vaccination against autologous cancer stem cells with mRNA-transfected dendritic cells in patients with glioblastoma. Cancer Immunol. Immunother.2013, 62, 1499–1509.
Li, Z. M.; Xu, W. G.; Yang, J. Z.; Wang, J.; Wang, J. L.; Zhu, G.; Li, D.; Ding, J. X.; Sun, T. M. A tumor microenvironments-adapted polypeptide hydrogel/nanogel composite boosts antitumor molecularly targeted inhibition and immunoactivation. Adv. Mater.2022, 34, 2200449.
Fogg, M. H.; Wirth, L. J.; Posner, M.; Wang, F. Decreased EBNA-1-specific CD8+ T cells in patients with Epstein–Barr virus-associated nasopharyngeal carcinoma. Proc. Natl. Acad. Sci. USA2009, 106, 3318–3323.
Dawson, C. W.; Port, R. J.; Young, L. S. The role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma (NPC). Semin. Cancer Biol.2012, 22, 144–153.
Zhu, S. L.; Chen, J.; Xiong, Y. R.; Kamara, S.; Gu, M. P.; Tang, W. L.; Chen, S.; Dong, H. Y.; Xue, X. Y.; Zheng, Z. M. et al. Novel EBV LMP-2-affibody and affitoxin in molecular imaging and targeted therapy of nasopharyngeal carcinoma. PLoS Pathog.2020, 16, e1008223.
Meij, P.; Leen, A.; Rickinson, A. B.; Verkoeijen, S.; Vervoort, M. B. H. J.; Bloemena, E.; Middeldorp, J. M. Identification and prevalence of CD8+ T-cell responses directed against Epstein–Barr virus-encoded latent membrane protein 1 and latent membrane protein 2. Int. J. Cancer2002, 99, 93–99.
Lei, L.; Li, J. H.; Liu, M. Q.; Hu, X. M.; Zhou, Y.; Yang, S. M. CD40L-adjuvanted DNA vaccine carrying EBV-LMP2 antigen enhances anti-tumor effect in NPC transplantation tumor animal. Cent. Eur. J. Immunol.2018, 43, 117–122.
Si, Y. F.; Deng, Z. X.; Lan, G. P.; Du, H. J.; Wang, Y. L.; Si, J. Y.; Wei, J. Z.; Weng, J. J.; Qin, Y. D.; Huang, B. et al. The safety and immunological effects of rAd5-EBV-LMP2 vaccine in nasopharyngeal carcinoma patients: A phase I clinical trial and two-year follow-up. Chem. Pharm. Bull.2016, 64, 1118–1123.
Lao, T. D.; Le, T. A. H. Association between LMP-1, LMP-2, and miR-155 expression as potential biomarker in nasopharyngeal carcinoma patients: A case/control study in Vietnam. Genet. Test. Mol. Biomarkers2019, 23, 815–822.
Xu, X. Y.; Xie, K.; Zhang, X. Q.; Pridgen, E. M.; Park, G. Y.; Cui, D. S.; Shi, J. J.; Wu, J.; Kantoff, P. W.; Lippard, S. J. et al. Enhancing tumor cell response to chemotherapy through nanoparticle-mediated codelivery of siRNA and cisplatin prodrug. Proc. Natl. Acad. Sci. USA2013, 110, 18638–18643.
Pollard, C.; Rejman, J.; De Haes, W.; Verrier, B.; Van Gulck, E.; Naessens, T.; De Smedt, S.; Bogaert, P.; Grooten, J.; Vanham, G. et al. Type I IFN counteracts the induction of antigen-specific immune responses by lipid-based delivery of mRNA vaccines. Mol. Ther.2013, 21, 251–259.
Brooks, L.; Yao, Q. Y.; Rickinson, A. B.; Young, L. S. Epstein–Barr virus latent gene transcription in nasopharyngeal carcinoma cells: Coexpression of EBNA1, LMP1, and LMP2 transcripts. J. Virol.1992, 66, 2689–2697.
Wang, F. Z.; Xiao, W.; Elbahnasawy, M. A.; Bao, X. T.; Zheng, Q.; Gong, L. H.; Zhou, Y.; Yang, S. P.; Fang, A. P.; Farag, M. M. S. et al. Optimization of the linker length of mannose-cholesterol conjugates for enhanced mRNA delivery to dendritic cells by liposomes. Front. Pharmacol.2018, 9, 980.
Ruso, J. M.; Besada, L.; Martínez-Landeira, P.; Seoane, L.; Prieto, G.; Sarmiento, F. Interactions between liposomes and cations in aqueous solution. J. Liposome Res.2003, 13, 131–145.
Latchumanan, V. K.; Singh, B.; Sharma, P.; Natarajan, K. Mycobacteriumtuberculosis antigens induce the differentiation of dendritic cells from bone marrow. J. Immunol. 2002, 169, 6856–6864.
[40]
Lou, B.; De Koker, S.; Lau, C. Y. J.; Hennink, W. E.; Mastrobattista, E. mRNA polyplexes with post-conjugated GALA peptides efficiently target, transfect, and activate antigen presenting cells. BioconjugateChem. 2019, 30, 461–475.
[41]
Wang, Y.; Zhang, Z. Q.; Luo, J. W.; Han, X. J.; Wei, Y. Q.; Wei, X. W. mRNA vaccine: A potential therapeutic strategy. Mol. Cancer2021, 20, 33.
[42]
Huang, S. C. M.; Tsao, S. W.; Tsang, C. M. Interplay of viral infection, host cell factors and tumor microenvironment in the pathogenesis of nasopharyngeal carcinoma. Cancers2018, 10, 106.
Feng, X. R.; Xu, W. G.; Liu, J. H.; Li, D.; Li, G.; Ding, J. X.; Chen, X. S. Polypeptide nanoformulation-induced immunogenic cell death and remission of immunosuppression for enhanced chemoimmunotherapy. Sci. Bull.2021, 66, 362–373.
Zheng, P.; Ding, B. B.; Jiang, Z. Y.; Xu, W. G.; Li, G.; Ding, J. X.; Chen, X. S. Ultrasound-augmented mitochondrial calcium ion overload by calcium nanomodulator to induce immunogenic cell death. Nano Lett.2021, 21, 2088–2093.
Zhao, Y. S.; Deng, J.; Rao, S. F.; Guo, S. P.; Shen, J.; Du, F. K.; Wu, X.; Chen, Y.; Li, M. X.; Chen, M. J. et al. Tumor infiltrating lymphocyte (TIL) therapy for solid tumor treatment: Progressions and challenges. Cancers2022, 14, 4160.
Ono, T.; Azuma, K.; Kawahara, A.; Sasada, T.; Matsuo, N.; Kakuma, T.; Kamimura, H.; Maeda, R.; Hattori, C.; On, K. et al. Prognostic stratification of patients with nasopharyngeal carcinoma based on tumor immune microenvironment. Head Neck2018, 40, 2007–2019.
Jin, S. Z.; Li, R. Y.; Chen, M. Y.; Yu, C.; Tang, L. Q.; Liu, Y. M.; Li, J. P.; Liu, Y. N.; Luo, Y. L.; Zhao, Y. F. et al. Single-cell transcriptomic analysis defines the interplay between tumor cells, viral infection, and the microenvironment in nasopharyngeal carcinoma. Cell Res.2020, 30, 950–965.
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