Abstract
Nucleic acid-based adjuvants have recently emerged as promising candidates for use in cancer vaccines to induce tumor-suppressing immune cells. In this study, we tested whether complexation of a nucleic acid-based adjuvant with chitosan (CTS) modulates immune adjuvant functions. As a nucleic acid-based adjuvant, we used toll-like receptor 3-recognizing RNA adjuvant (RA). Negatively charged RA formed nanoscale polyplexes with cationic CTS that possessed positive zeta potentials. RA/CTS polyplexes exerted dendritic cell (DC)-maturation effects without causing significant DC toxicity. This DC-maturation effect was CTS molecular weight dependent, with RA/CTS polyplexes with a CTS molecular weight of 340 kDa (RA/CTS 340K) producing the greatest effect. Subcutaneous injection of RA/CTS 340K polyplexes with the model tumor antigen ovalbumin exerted a preventive effect against challenge by ovalbumin-expressing tumor cells. It also provided greater inhibitory effects against a second challenge with the same tumor cells compared with other treatments. These protective effects of subcutaneous RA/CTS polyplex treatment were associated with the highest tumor antigen-specific humoral and cellular immune responses after tumor challenge, and with the greatest infiltration of CD4 helper T cell and CD8 T cell into the tumor tissues. Mice vaccinated with ovalbumin and RA/CTS polyplexes showed complete survival, even after repeated challenge with tumor cells. Our results suggest the potential of RA/CTS polyplexes as effective nanoadjuvants in the design of tumor vaccines and cancer immunotherapy.
Highlights
Cancer vaccines have been extensively studied for their potential to stimulate active antitumor immunity to fight against cancers [1]
In vivo anticancer efficacy was tested after immunizing naïve C57BL/6 mice with 100 μg CTS or with RNA adjuvant (RA)/CTS polyplexes with a RA:CTS weight ratio of 1:10, and subsequently challenging with B16-OVA cells, a B16F10 tumor cell line stably transfected with OVA-encoding plasmid DNA
The formation and physicochemical properties of RA/CTS polyplexes were characterized by gel retardation, and measurement of size, zeta potential, and morphology
Summary
Cancer vaccines have been extensively studied for their potential to stimulate active antitumor immunity to fight against cancers [1]. For the design of effective cancer vaccines, there is a need for new adjuvants that can boost cellular immune responses. CpG and poly I:C are representative nucleic acid adjuvants that are capable of generating cytotoxic T lymphocytes, resulting in killing effects towards tumor cells [4,5,6]. Despite progress in this area, clinical trials of nucleic acid adjuvants for cancer vaccines have still shown insufficient preventive effects [7]. SchSecmhaetmicaitlilcusitlrlautsiotrnatoiofnRAo/fCTRSA/(CRTNSA (aRdNjuAvanatd/cjuhvitaonsat/nch) iptooslaynp)lexpeoslyapsleaxnesimamsunaenimmomduunlaet-imngodaudlajutivnagnatdfjuorvacnatnfcoerrcainmcmeruinmomthuenraopthye.ra(Apy). (RAA) RwAaws acsocmopmlepxleexdedwwitihthCCTTSS tthhrroouugghh eelleeccttrroossttaattiicciinntteerraaccttiioonnssttooffoorrmmRRAA//CCTTSSppoollyypplleexxeess..((BB))SSuubbccuuttaanneeoouussiinnjjeeccttiioonnooff RRAA//CCTTSSttooggeetthheerr wwiitthhoovvaalblbuumminin(O(OVAV)Aa)ntaingteingeanctiavcattievsatdeesndderintidcrciteilclsc(eDllCss()D, iCnds)u, ciinndgutchienigr mthigeriratmioingtroatnioenarbtoy nlyemarpbhy nlyomdepshfonrosduebssfeoqruseunbtsaenqutiegnetnapnrteigseenntpatrieosne.nNtaatiïovne.TNcaeïlvlse pTrceeslelns tperdesweintthedanwtiigthenaenptiigtoenpeespvitioapmesajvoira hmisatojocromhipstaotciboimlitpyactoibmilpitlyexcoI m(MpHleCx-II) (mMoHleCcu-Il)esmaonldeccuol-esstimaunladtocroy-sstiigmnuallsatcoornysesqiguneanltslycdoniffseerqeunetinattley idnitfofeOreVnAti-astpeeicnitfiocOcyVtAot-ospxiecciTficceclylst.ot(oCx)iTc hTecseellcsy. t(oCt)oTxhiceTsecceylltsotaorxeiccaTpcaebllles aorfekciallpinagblOe oVfAk-iellxipnrgeOssVinAgteuxmporerscseinllgs,tfuumncotriocneilnlsg, fausnactpiorenvinengtaivseacparnecveernvtaivcecicnaen. cer vaccine
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