Skip to main content

Advertisement

SpringerLink
Log in

Paracrine release of IL-2 and anti-CTLA-4 enhances the ability of artificial polymer antigen-presenting cells to expand antigen-specific T cells and inhibit tumor growth in a mouse model

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Accumulating evidence indicates that bead-based artificial antigen-presenting cells (aAPCs) are a powerful tool to induce antigen-specific T cell responses in vitro and in vivo. To date, most conventional aAPCs have been generated by coupling an antigen signal (signal 1) and one or two costimulatory signals, such as anti-CD28 with anti-LFA1 or anti-4-1BB (signal 2), onto the surfaces of cell-sized or nanoscale magnetic beads or polyester latex beads. The development of a biodegradable scaffold and the combined use of multiple costimulatory signals as well as third signals for putative clinical applications is the next step in the development of this technology. Here, a novel biodegradable aAPC platform for active immunotherapy was developed by co-encapsulating IL-2 and anti-CTLA-4 inside cell-sized polylactic-co-glycolic acid microparticles (PLGA-MPs) while co-coupling an H-2Kb/TRP2-Ig dimer and anti-CD28 onto the surface. Cytokines (activating signal) and antibodies (anti-inhibition signal) were efficiently co-encapsulated in PLGA-MP-based aAPCs and co-released without interfering with each other. The targeted, sustained co-release of IL-2 and anti-CTLA-4 achieved markedly enhanced, synergistic effects in activating and expanding tumor antigen-specific T cells both in vitro and in vivo, as well as in inhibiting tumor growth in a mouse melanoma model, as compared with conventional two-signal aAPCs and IL-2 or anti-CTLA-4 single-released aAPCs. These data revealed the feasibility and importance of the paracrine release of multiple costimulatory molecules and cytokines from biodegradable aAPCs and thus provide a proof of principle for the future use of polymeric aAPCs for active immunotherapy of tumors and infectious diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

7-AAD:

7-amino-actinomycin D

aAPCs:

Artificial antigen-presenting cells

MNPs:

Micro- and nanoparticles

MPs:

Microparticles

PEI:

Polyethylenimine

PLGA:

Polylactic-co-glycolic acid

pMHC:

Peptide-major histocompatibility complex

TRP2:

Tyrosinase-related protein 2

References

  1. Lee SJ, Yang A, Wu TC, Hung CF (2016) Immunotherapy for human papillomavirus-associated disease and cervical cancer: review of clinical and translational research. J Gynecol Oncol 27(5):e51. doi:10.3802/jgo.2016.27.e51

    Article  PubMed  PubMed Central  Google Scholar 

  2. Snell LM, Osokine I, Yamada DH, De la Fuente JR, Elsaesser HJ, Brooks DG (2016) Overcoming CD4 Th1 cell fate restrictions to sustain antiviral CD8 T cells and control persistent virus infection. Cell Rep 16(12):3286–3296. doi:10.1016/j.celrep.2016.08.065

    Article  CAS  PubMed  Google Scholar 

  3. Hu Z, Xia J, Fan W, Wargo J, Yang YG (2016) Human melanoma immunotherapy using tumor antigen-specific T cells generated in humanized mice. Oncotarget 7(6):6448–6459. doi:10.18632/oncotarget.7044

    Article  PubMed  PubMed Central  Google Scholar 

  4. Osada T, Nagaoka K, Takahara M, Yang XY, Liu CX, Guo H, Roy Choudhury K, Hobeika A, Hartman Z, Morse MA, Lyerly HK (2015) Precision cancer immunotherapy: optimizing dendritic cell-based strategies to induce tumor antigen-specific T-cell responses against individual patient tumors. J Immunother 38(4):155–164. doi:10.1097/CJI.0000000000000075

    Article  CAS  PubMed  Google Scholar 

  5. Zhang N, Bevan MJ (2011) CD8(+) T cells: foot soldiers of the immune system. Immunity 35(2):161–168. doi:10.1016/j.immuni.2011.07.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bhargava A, Mishra D, Banerjee S, Mishra PK (2012) Dendritic cell engineering for tumor immunotherapy: from biology to clinical translation. Immunotherapy 4(7):703–718. doi:10.2217/Imt.12.40

    Article  CAS  PubMed  Google Scholar 

  7. Bol KF, Schreibelt G, Gerritsen WR, de Vries IJ, Figdor CG (2016) Dendritic cell-based immunotherapy: state of the art and beyond. Clin Cancer Res 22(8):1897–1906. doi:10.1158/1078-0432.CCR-15-1399

    Article  CAS  PubMed  Google Scholar 

  8. Kim JV, Latouche JB, Riviere I, Sadelain M (2004) The ABCs of artificial antigen presentation. Nat Biotechnol 22(4):403–410. doi:10.1038/nbt955

    Article  CAS  PubMed  Google Scholar 

  9. Butler MO, Hirano N (2014) Human cell-based artificial antigen-presenting cells for cancer immunotherapy. Immunol Rev 257(1):191–209. doi:10.1111/imr.12129

    Article  CAS  PubMed  Google Scholar 

  10. Eggermont LJ, Paulis LE, Tel J, Figdor CG (2014) Towards efficient cancer immunotherapy: advances in developing artificial antigen-presenting cells. Trends Biotechnol 32(9):456–465. doi:10.1016/j.tibtech.2014.06.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Goto T, Nishida T, Takagi E, Miyao K, Koyama D, Sakemura R, Hanajiri R, Watanabe K, Imahashi N, Terakura S, Murata M, Kiyoi H (2016) Programmed death-ligand 1 on antigen-presenting cells facilitates the induction of antigen-specific cytotoxic T lymphocytes: application to adoptive T-cell immunotherapy. J Immunother 39(8):306–315. doi:10.1097/CJI.0000000000000136

    Article  CAS  PubMed  Google Scholar 

  12. Sun L, Guo H, Jiang R, Lu L, Liu T, Zhang Z, He X (2016) Artificial antigen-presenting cells expressing AFP(158-166) peptide and interleukin-15 activate AFP-specific cytotoxic T lymphocytes. Oncotarget 7(14):17579–17590. doi:10.18632/oncotarget.8198

    Article  PubMed  PubMed Central  Google Scholar 

  13. Garnier A, Hamieh M, Drouet A, Leprince J, Vivien D, Frebourg T, Le Mauff B, Latouche JB, Toutirais O (2016) Artificial antigen-presenting cells expressing HLA class II molecules as an effective tool for amplifying human specific memory CD4(+) T cells. Immunol Cell Biol 94(7):662–672. doi:10.1038/icb.2016.25

    Article  CAS  PubMed  Google Scholar 

  14. Perica K, Kosmides AK, Schneck JP (2014) Linking form to function: biophysical aspects of artificial antigen presenting cell design. Biochim Biophys Acta 1853(4):781–790. doi:10.1016/j.bbamcr.2014.09.001

    Article  PubMed  PubMed Central  Google Scholar 

  15. Bruns H, Bessell C, Varela JC, Haupt C, Fang J, Pasemann S, Mackensen A, Oelke M, Schneck JP, Schutz C (2015) CD47 enhances in vivo functionality of artificial antigen-presenting cells. Clin Cancer Res 21(9):2075–2083. doi:10.1158/1078-0432.CCR-14-2696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Perica K, Bieler JG, Schutz C, Varela JC, Douglass J, Skora A, Chiu YL, Oelke M, Kinzler K, Zhou S, Vogelstein B, Schneck JP (2015) Enrichment and expansion with nanoscale artificial antigen presenting cells for adoptive immunotherapy. ACS Nano 9(7):6861–6871. doi:10.1021/acsnano.5b02829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Durai M, Krueger C, Ye Z, Cheng L, Mackensen A, Oelke M, Schneck JP (2009) In vivo functional efficacy of tumor-specific T cells expanded using HLA-Ig based artificial antigen presenting cells (aAPC). Cancer Immunol Immunother 58(2):209–220. doi:10.1007/s00262-008-0542-1

    Article  CAS  PubMed  Google Scholar 

  18. Lu XL, Jiang XB, Liu RE, Zhang SM, Liang ZH (2009) In vivo anti-melanoma efficacy of allo-restricted CTLs specific for melanoma expanded by artificial antigen-presenting cells. Cancer Immunol Immunother 58(4):629–638. doi:10.1007/s00262-008-0573-7

    Article  CAS  PubMed  Google Scholar 

  19. Chiu YL, Schneck JP, Oelke M (2011) HLA-Ig based artificial antigen presenting cells for efficient ex vivo expansion of human CTL. J Vis Exp. doi:10.3791/2801

    Google Scholar 

  20. Shen C, Cheng K, Miao S, Wang W, He Y, Meng F, Zhang J (2013) Latex bead-based artificial antigen-presenting cells induce tumor-specific CTL responses in the native T-cell repertoires and inhibit tumor growth. Immunol Lett 150(1–2):1–11. doi:10.1016/j.imlet.2013.01.003

    Article  CAS  PubMed  Google Scholar 

  21. Han FY, Thurecht KJ, Whittaker AK, Smith MT (2016) Bioerodable PLGA-based microparticles for producing sustained-release drug formulations and strategies for improving drug loading. Front Pharmacol 7:185. doi:10.3389/fphar.2016.00185

    Article  PubMed  PubMed Central  Google Scholar 

  22. Pagels RF, Prud’homme RK (2015) Polymeric nanoparticles and microparticles for the delivery of peptides, biologics, and soluble therapeutics. J Control Release 219:519–535. doi:10.1016/j.jconrel.2015.09.001

    Article  CAS  PubMed  Google Scholar 

  23. Iqbal M, Zafar N, Fessi H, Elaissari A (2015) Double emulsion solvent evaporation techniques used for drug encapsulation. Int J Pharm 496(2):173–190. doi:10.1016/j.ijpharm.2015.10.057

    Article  CAS  PubMed  Google Scholar 

  24. Shah SR, Henslee AM, Spicer PP, Yokota S, Petrichenko S, Allahabadi S, Bennett GN, Wong ME, Kasper FK, Mikos AG (2014) Effects of antibiotic physicochemical properties on their release kinetics from biodegradable polymer microparticles. Pharm Res 31(12):3379–3389. doi:10.1007/s11095-014-1427-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Donat U, Rother J, Schäfer S, Hess M, Härtl B, Kober C, Langbein-Laugwitz J, Stritzker J, Chen NG, Aguilar RJ (2014) Characterization of metastasis formation and virotherapy in the human C33A cervical cancer model. PLoS One 9(6):e98533. doi:10.1371/journal.pone.0098533

    Article  PubMed  PubMed Central  Google Scholar 

  26. Geekiyanage H, Galanis E (2016) MiR-31 and miR-128 regulates poliovirus receptor-related 4 mediated measles virus infectivity in tumors. Mol Oncol 10(9):1387–1403. doi:10.1016/j.molonc.2016.07.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang W, Fang K, Li MC, Chang D, Shahzad KA, Xu T, Zhang L, Gu N, Shen CL (2016) A biodegradable killer microparticle to selectively deplete antigen-specific T cells in vitro and in vivo. Oncotarget 7(11):12176–12190. doi:10.18632/oncotarget.7519

    Article  PubMed  PubMed Central  Google Scholar 

  28. He C, Ma H, Cheng Y, Li D, Gong Y, Liu J, Tian H, Chen X (2015) PLK1shRNA and doxorubicin co-loaded thermosensitive PLGA-PEG-PLGA hydrogels for localized and combined treatment of human osteosarcoma. J Control Release 213:e18. doi:10.1016/j.jconrel.2015.05.026

    Article  PubMed  Google Scholar 

  29. Steenblock ER, Fadel T, Labowsky M, Pober JS, Fahmy TM (2011) An artificial antigen-presenting cell with paracrine delivery of IL-2 impacts the magnitude and direction of the T cell response. J Biol Chem 286(40):34883–34892. doi:10.1074/jbc.M111.276329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Han H, Peng JR, Chen PC, Gong L, Qiao SS, Wang WZ, Cui ZQ, Yu X, Wei YH, Leng XS (2011) A novel system of artificial antigen-presenting cells efficiently stimulates Flu peptide-specific cytotoxic T cells in vitro. Biochem Biophys Res Commun 411(3):530–535. doi:10.1016/j.bbrc.2011.06.164

    Article  CAS  PubMed  Google Scholar 

  31. Steenblock ER, Fahmy TM (2008) A comprehensive platform for ex vivo T-cell expansion based on biodegradable polymeric artificial antigen-presenting cells. Mol Ther 16(4):765–772. doi:10.1038/mt.2008.11

    Article  CAS  PubMed  Google Scholar 

  32. Sunshine JC, Perica K, Schneck JP, Green JJ (2014) Particle shape dependence of CD8 + T cell activation by artificial antigen presenting cells. Biomaterials 35(1):269–277. doi:10.1016/j.biomaterials.2013.09.050

    Article  CAS  PubMed  Google Scholar 

  33. Meyer RA, Sunshine JC, Perica K, Kosmides AK, Aje K, Schneck JP, Green JJ (2015) Biodegradable nanoellipsoidal artificial antigen presenting cells for antigen specific T-cell activation. Small 11(13):1519–1525. doi:10.1002/smll.201402369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jiang T, Zhou C, Ren S (2016) Role of IL-2 in cancer immunotherapy. Oncoimmunology 5(6):e1163462. doi:10.1080/2162402X.2016.1163462

    Article  PubMed  PubMed Central  Google Scholar 

  35. Baumeister SH, Freeman GJ, Dranoff G, Sharpe AH (2016) Coinhibitory pathways in immunotherapy for cancer. Annu Rev Immunol 34:539–573. doi:10.1146/annurev-immunol-032414-112049

    Article  CAS  PubMed  Google Scholar 

  36. Khoja L, Atenafu EG, Ye Q, Gedye C, Chappell M, Hogg D, Butler MO, Joshua AM (2016) Real-world efficacy, toxicity and clinical management of ipilimumab treatment in metastatic melanoma. Oncol Lett 11(2):1581–1585. doi:10.3892/ol.2015.4069

    PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81172823, 81372448) and the Science and Technology Support Program of Jiangsu Province (BE2012739).

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, Medical School, Southeast University, 87 Dingjiaqiao Rd, Nanjing, 210009, Jiangsu, People’s Republic of China

    Lei Zhang, Limin Wang, Khawar Ali Shahzad, Tao Xu, Xin Wan, Weiya Pei & Chuanlai Shen

Authors
  1. Lei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Limin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Khawar Ali Shahzad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tao Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xin Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Weiya Pei
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chuanlai Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chuanlai Shen.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 944 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, L., Wang, L., Shahzad, K.A. et al. Paracrine release of IL-2 and anti-CTLA-4 enhances the ability of artificial polymer antigen-presenting cells to expand antigen-specific T cells and inhibit tumor growth in a mouse model. Cancer Immunol Immunother 66, 1229–1241 (2017). https://doi.org/10.1007/s00262-017-2016-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-017-2016-9

Keywords

Search

Navigation