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Cancer Immunology, Immunotherapy

Published in:

09-01-2023 | Gastric Cancer | Research

A nanotherapeutic system for gastric cancer suppression by synergistic chemotherapy and immunotherapy based on iPSCs and DCs exosomes

Authors: Yezhou Li, Leilei Tian, Tiancheng Zhao, Jiayu Zhang

Published in: Cancer Immunology, Immunotherapy | Issue 6/2023

Abstract

Background

Chemotherapeutic drugs, the indispensable therapy in the treatment of gastric cancer, contain many problems such as high organ toxicity and insufficient therapeutic effect. The development of nanodrug delivery carriers with both tumor targeting function and immune stimulation ability possesses the potential to remedy these practical defects.

Methods and results

In this study, a tumor targeting nanosystem that combines chemotherapy with immunotherapy was applied to the treatment and prognosis of gastric cancer. The fusion vector of iPSCs and DCs exosomes, which simultaneously possess the ability of tumor targeting and immune factor recruitment, effectively improved the in vivo efficacy of chemotherapy drugs and released the suppressed T lymphocytes under the action of modified PD-1 antibody to dredge the immunotherapy process. In addition, extensive recruitment of immune cells to clean the environment while exposing vast tumor antigens efficiently amplified the anti-tumor immune effect and ensured the good prognosis.

Conclusions

Nanodrug delivery system DOX@aiPS-DCexo could effectively inhibit the expansion process of gastric cancer MFC through synergistic chemotherapy and immunotherapy and demonstrated the capacity of improving prognosis.

Graphical Abstract

Scheme: schematic illustration of the nanostructure DOX@aiPS-DCexo and the mechanism of action.

Wagner AD, Syn NLX, Moehler M et al (2017) Chemotherapy for advanced gastric cancer. Cochrane database Syst Rev. https://doi.org/10.1002/14651858.CD004064.PUB4CrossRefPubMedPubMedCentral

Joshi SS, Badgwell BD (2021) Current treatment and recent progress in gastric cancer. CA Cancer J Clin 71:264–279. https://doi.org/10.3322/CAAC.21657CrossRefPubMedPubMedCentral

Thrift AP, El-Serag HB (2020) Burden of gastric cancer. Clin Gastroenterol Hepatol 18:534–542. https://doi.org/10.1016/J.CGH.2019.07.045CrossRefPubMed

Wang A, Li Z, Wang M et al (2020) Molecular characteristics of synchronous multiple gastric cancer. Theranostics 10:5489–5500. https://doi.org/10.7150/THNO.42814CrossRefPubMedPubMedCentral

Moss SF (2017) The clinical evidence linking helicobacter pylori to gastric cancer. CMGH 3:183–191. https://doi.org/10.1016/J.JCMGH.2016.12.001CrossRefPubMed

Sa JK, Hong JY, Lee IK et al (2020) Comprehensive pharmacogenomic characterization of gastric cancer. Genome Med. https://doi.org/10.1186/S13073-020-0717-8CrossRefPubMedPubMedCentral

Diaz-Nieto R, Orti-Rodríguez R, Winslet M (2013) Post-surgical chemotherapy versus surgery alone for resectable gastric cancer. Cochrane database Syst Rev. https://doi.org/10.1002/14651858.CD008415.PUB2CrossRefPubMed

Stewart OA, Wu F, Chen Y (2020) The role of gastric microbiota in gastric cancer. Gut Microbes 11:1220–1230. https://doi.org/10.1080/19490976.2020.1762520CrossRefPubMedPubMedCentral

Li R, Hou WH, Chao J et al (2018) Chemoradiation improves survival compared with chemotherapy alone in unresected nonmetastatic gastric cancer. J Natl Compr Cancer Netw 16:950–958. https://doi.org/10.6004/JNCCN.2018.7030CrossRef

10.

Carmona-Bayonas A, Jiménez-Fonseca P, Lorenzo MLS et al (2016) On the effect of triplet or doublet chemotherapy in advanced gastric cancer: results from a national cancer registry. J Natl Compr Cancer Netw 14:1379–1388. https://doi.org/10.6004/JNCCN.2016.0148CrossRef

11.

Wang F, Porter M, Konstantopoulos A et al (2017) Preclinical development of drug delivery systems for paclitaxel-based cancer chemotherapy. J Control Release 267:100–118. https://doi.org/10.1016/J.JCONREL.2017.09.026CrossRefPubMedPubMedCentral

12.

Shafabakhsh R, Yousefi B, Asemi Z et al (2020) Chitosan: a compound for drug delivery system in gastric cancer-a review. Carbohydr Polym. https://doi.org/10.1016/J.CARBPOL.2020.116403CrossRefPubMed

13.

Li K, Zhang A, Li X et al (2021) Advances in clinical immunotherapy for gastric cancer. Biochim Biophys Acta Rev Cancer. https://doi.org/10.1016/J.BBCAN.2021.188615CrossRefPubMed

14.

Hußtegge M, Hoang NA, Rebstock J et al (2021) PD-1 inhibition in patient derived tissue cultures of human gastric and gastroesophageal adenocarcinoma. Oncoimmunology. https://doi.org/10.1080/2162402X.2021.1960729CrossRefPubMedPubMedCentral

15.

Li Q, Zhou ZW, Lu J et al (2022) PD-L1 P146R is prognostic and a negative predictor of response to immunotherapy in gastric cancer. Mol Ther 30:621–631. https://doi.org/10.1016/J.YMTHE.2021.09.013CrossRefPubMed

16.

Umeda S, Kanda M, Shimizu D et al (2022) Lysosomal-associated membrane protein family member 5 promotes the metastatic potential of gastric cancer cells. Gastric Cancer. https://doi.org/10.1007/S10120-022-01284-YCrossRefPubMed

17.

Kamada T, Togashi Y, Tay C et al (2019) PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc Natl Acad Sci USA 116:9999–10008. https://doi.org/10.1073/PNAS.1822001116/-/DCSUPPLEMENTALCrossRefPubMedPubMedCentral

18.

Hu X, Wang J, Chu M et al (2021) Emerging Role of ubiquitination in the Regulation of PD-1/PD-L1 in Cancer Immunotherapy. Mol Ther 29:908–919. https://doi.org/10.1016/J.YMTHE.2020.12.032CrossRefPubMedPubMedCentral

19.

Li C, Ruan J, Yang M et al (2015) Human induced pluripotent stem cells labeled with fluorescent magnetic nanoparticles for targeted imaging and hyperthermia therapy for gastric cancer. Cancer Biol Med 12:163–174. https://doi.org/10.7497/J.ISSN.2095-3941.2015.0040CrossRefPubMedPubMedCentral

20.

Ehtesham M, Yuan X, Kabos P et al (2004) Glioma tropic neural stem cells consist of astrocytic precursors and their migratory capacity is mediated by CXCR4. Neoplasia 6:287–293. https://doi.org/10.1593/NEO.3427CrossRefPubMedPubMedCentral

21.

Molyneaux KA, Zinszner H, Kunwar PS et al (2003) The chemokine SDF1/CXCL12 and its receptor CXCR4 regulate mouse germ cell migration and survival. Development 130:4279–4286. https://doi.org/10.1242/DEV.00640CrossRefPubMed

22.

Ceradini DJ, Kulkarni AR, Callaghan MJ et al (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858–864. https://doi.org/10.1038/NM1075CrossRefPubMed

23.

Lee EX, Lam DH, Wu C et al (2011) Glioma gene therapy using induced pluripotent stem cell derived neural stem cells. Mol Pharm 8:1515–1524. https://doi.org/10.1021/MP200127UCrossRefPubMed

24.

Yang J, Lam DH, Goh SS et al (2012) Tumor tropism of intravenously injected human-induced pluripotent stem cell-derived neural stem cells and their gene therapy application in a metastatic breast cancer model. Stem Cells 30:1021–1029. https://doi.org/10.1002/STEM.1051CrossRefPubMed

25.

Koizumi S, Gu C, Amano S et al (2011) Migration of mouse-induced pluripotent stem cells to glioma-conditioned medium is mediated by tumor-associated specific growth factors. Oncol Lett 2:283–288. https://doi.org/10.3892/OL.2011.234CrossRefPubMedPubMedCentral

26.

Li W, Zhang X, Wu F et al (2019) Gastric cancer-derived mesenchymal stromal cells trigger M2 macrophage polarization that promotes metastasis and EMT in gastric cancer. Cell Death Dis. https://doi.org/10.1038/S41419-019-2131-YCrossRefPubMedPubMedCentral

27.

Gao W, Liu H, Yuan J et al (2016) Exosomes derived from mature dendritic cells increase endothelial inflammation and atherosclerosis via membrane TNF-α mediated NF-κB pathway. J Cell Mol Med 20:2318–2327. https://doi.org/10.1111/JCMM.12923CrossRefPubMedPubMedCentral

28.

Fu C, Zhou L, Mi QS, Jiang A (2020) Dc-based vaccines for cancer immunotherapy. Vaccines 8:1–16. https://doi.org/10.3390/VACCINES8040706CrossRef

29.

Pitt JM, André F, Amigorena S et al (2016) Dendritic cell-derived exosomes for cancer therapy. J Clin Invest 126:1224–1232. https://doi.org/10.1172/JCI81137CrossRefPubMedPubMedCentral

30.

Yao Y, Fu C, Zhou L et al (2021) Dc-derived exosomes for cancer immunotherapy. Cancers (Basel). https://doi.org/10.3390/CANCERS13153667CrossRefPubMedPubMedCentral

31.

Familtseva A, Jeremic N, Tyagi SC (2019) Exosomes: cell-created drug delivery systems. Mol Cell Biochem. https://doi.org/10.1007/S11010-019-03545-4CrossRefPubMed

32.

Liang Y, Duan L, Lu J, Xia J (2021) Engineering exosomes for targeted drug delivery. Theranostics 11:3183–3195. https://doi.org/10.7150/THNO.52570CrossRefPubMedPubMedCentral

33.

Zhong H, Yang Y, Ma S et al (2011) Induction of a tumour-specific CTL response by exosomes isolated from heat-treated malignant ascites of gastric cancer patients. Int J Hyperth 27:604–611. https://doi.org/10.3109/02656736.2011.564598CrossRef

34.

Liu J, Ren L, Li S et al (2021) The biology, function, and applications of exosomes in cancer. Acta Pharm Sin B 11:2783–2797. https://doi.org/10.1016/J.APSB.2021.01.001CrossRefPubMedPubMedCentral

35.

Chai Z, Ran D, Lu L et al (2019) Ligand-modified cell membrane enables the targeted delivery of drug nanocrystals to glioma. ACS Nano. https://doi.org/10.1021/ACSNANO.9B00661CrossRefPubMed

36.

Song X, Jiang Y, Zhang W et al (2022) Transcutaneous tumor vaccination combined with anti-programmed death-1 monoclonal antibody treatment produces a synergistic antitumor effect. Acta Biomater 140:247–260. https://doi.org/10.1016/j.actbio.2021.11.033CrossRefPubMed

37.

Jiang M, Chen W, Yu W et al (2021) Sequentially pH-responsive drug-delivery nanosystem for tumor immunogenic cell death and cooperating with immune checkpoint blockade for efficient cancer chemoimmunotherapy. ACS Appl Mater Interfaces 13:43963–43974. https://doi.org/10.1021/acsami.1c10643CrossRefPubMed

38.

Shao J, Zaro J, Shen Y (2020) Advances in exosome-based drug delivery and tumor targeting: from tissue distribution to intracellular fate. Int J Nanomed 15:9355–9371. https://doi.org/10.2147/IJN.S281890CrossRef

39.

Wang S, Ping M, Song B et al (2020) Exosomal circPRRX1 enhances doxorubicin resistance in gastric cancer by regulating mir-3064-5p/PTPN14 signaling. Yonsei Med J 61:750–761. https://doi.org/10.3349/YMJ.2020.61.9.750CrossRefPubMedPubMedCentral

40.

Razavi SMS, Vaziri RM, Karimi G et al (2020) Crocin increases gastric cancer cells’ sensitivity to doxorubicin. Asian Pacific J Cancer Prev 21:1959–1967. https://doi.org/10.31557/APJCP.2020.21.7.1959CrossRef

41.

Xu J, Liu D, Niu H et al (2017) Resveratrol reverses doxorubicin resistance by inhibiting epithelial-mesenchymal transition (EMT) through modulating PTEN/Akt signaling pathway in gastric cancer. J Exp Clin Cancer Res. https://doi.org/10.1186/S13046-016-0487-8CrossRefPubMedPubMedCentral

Title: A nanotherapeutic system for gastric cancer suppression by synergistic chemotherapy and immunotherapy based on iPSCs and DCs exosomes
Authors: Yezhou Li
Leilei Tian
Tiancheng Zhao
Jiayu Zhang
Publication date: 09-01-2023
Publisher: Springer Berlin Heidelberg
Keywords: Gastric Cancer
Gastric Cancer
Cytostatic Therapy
Published in: Cancer Immunology, Immunotherapy / Issue 6/2023
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-022-03355-6

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Abstract

Background

Methods and results

Conclusions

Graphical Abstract

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