Dendritic cells loaded with CD44+ CT‑26 colon cell lysate evoke potent antitumor immune responses

Fu,Changhao; Zhou,Ning; Zhao,Yuanyuan; Duan,Jinyue; Xu,Hao; Wang,Yi

doi:10.3892/ol.2019.10952

Dendritic cells loaded with CD44+ CT‑26 colon cell lysate evoke potent antitumor immune responses

Authors:
- Changhao Fu
- Ning Zhou
- Yuanyuan Zhao
- Jinyue Duan
- Hao Xu
- Yi Wang
View Affiliations

Affiliations: Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
Published online on: October 2, 2019 https://doi.org/10.3892/ol.2019.10952
Pages: 5897-5904
Copyright: © Fu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Increasing evidence supports the concept that cancer stem cells (CSCs) are responsible for cancer progression and metastasis, therapy resistance and relapse. In addition to conventional therapies for colon cancer, the development of immunotherapies targeting cancer stem cells appears to be a promising strategy to suppress tumor recurrence and metastasis. In the present study, dendritic cells (DCs) were pulsed with whole‑tumor cell lysates or total RNA of CD44+ colon cancer stem cells (CCSCs) isolated from mouse colon adenocarcinoma CT‑26 cell cultures and investigated for their antitumor immunity against CCSCs in vivo and in vitro. In a model of colon adenocarcinoma using BALB/c mice, a sequential reduction in tumor volume and weight was associated with an extended survival in tumor‑bearing mice vaccinated with DCs pulsed with RNA or CCSC lysate. In addition, a lactate dehydrogenase assay indicated that cytotoxic T‑cells derived from the treated mice exhibited strong cytotoxic activity. Additionally, an enzyme‑linked immunosorbent assay revealed that the cytotoxic T‑cells of the treated mice released higher levels of interferon‑γ against CCSCs compared with those of the control group. In all experiments, the antitumor efficacy of the lysate‑pulsed DC‑treated and RNA‑pulsed DC‑treated groups were significantly higher compared with that of the DC‑treated and control groups. The results of the present study indicated the potential use of DCs pulsed with cancer stem cell lysates as a potent therapeutic antigen to target CSCs in colon cancer. Additionally, the results provided a rationale for using lysate‑pulsed DCs in vivo to eliminate residual tumor deposits in post‑operative patients.

View Figures

View References

1	American Cancer Society, . Cancer Facts and Figures 2019. Atlanta: American Cancer Society;2019. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2019/cancer-facts-and-figures-2019.pdfFebruary 20–2019
2	Van Cutsem E and Oliveira J: ESMO Guidelines Working Group: Advanced colorectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 20 (Suppl 4):S61–S63. 2009. View Article : Google Scholar
3	Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, Bhattacharya R, Gabrilovich D, Heller R, Coppola D, et al: Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med. 10:48–54. 2004. View Article : Google Scholar : PubMed/NCBI
4	Beatty GL and Gladney WL: Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res. 21:687–692. 2015. View Article : Google Scholar : PubMed/NCBI
5	Camus M, Tosolini M, Mlecnik B, Pagès F, Kirilovsky A, Berger A, Costes A, Bindea G, Charoentong P, Bruneval P, et al: Coordination of intratumoral immune reaction and human colorectal cancer recurrence. Cancer Res. 69:2685–2693. 2009. View Article : Google Scholar : PubMed/NCBI
6	Baier PK, Wimmenauer S, Hirsch T, von Specht BU, von Kleist S, Keller H and Farthmann EH: Analysis of the T cell receptor variability of tumor-infiltrating lymphocytes in colorectal carcinomas. Tumour Biol. 19:205–212. 1998. View Article : Google Scholar : PubMed/NCBI
7	Hsu FJ, Benike C, Fagnoni F, Liles TM, Czerwinski D, Taidi B, Engleman EG and Levy R: Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med. 2:52–58. 1996. View Article : Google Scholar : PubMed/NCBI
8	Rains N, Cannan RJ, Chen W and Stubbs RS: Development of a dendritic cell (DC)-based vaccine for patients with advanced colorectal cancer. Hepatogastroenterology. 48:347–351. 2001.PubMed/NCBI
9	Trombetta ES and Mellman I: Cell biology of antigen processing in vitro and in vivo. Annu Rev Immunol. 23:975–1028. 2005. View Article : Google Scholar : PubMed/NCBI
10	Datta J, Terhune JH, Lowenfeld L, Cintolo JA, Xu S, Roses RE and Czerniecki BJ: Optimizing dendritic cell-based approaches for cancer immunotherapy. Yale J Biol Med. 87:491–518. 2014.PubMed/NCBI
11	Anguille S, Smits EL, Lion E, van Tendeloo VF and Berneman ZN: Clinical use of dendritic cells for cancer therapy. Lancet Oncol. 15:e257–e267. 2014. View Article : Google Scholar : PubMed/NCBI
12	Wu YG, Wu GZ, Wang L, Zhang YY, Li Z and Li DC: Tumor cell lysate-pulsed dendritic cells induce a T cell response against colon cancer in vitro and in vivo. Med Oncol. 27:736–742. 2010. View Article : Google Scholar : PubMed/NCBI
13	Brown CE, Starr R, Martinez C, Aguilar B, D'Apuzzo M, Todorov I, Shih CC, Badie B, Hudecek M, Riddell SR and Jensen MC: Recognition and killing of brain tumor stem-like initiating cells by CD8+ cytolytic T cells. Cancer Res. 69:8886–8893. 2009. View Article : Google Scholar : PubMed/NCBI
14	Yang S, Darrow TL, Vervaert CE and Seigler HF: Immunotherapeutic potential of tumor antigen-pulsed and unpulsed dendritic cells generated from murine bone marrow. Cell Immunol. 179:84–95. 1997. View Article : Google Scholar : PubMed/NCBI
15	Vlashi E and Pajonk F: Cancer stem cells, cancer cell plasticity and radiation therapy. Semin Cancer Biol. 31:28–35. 2015. View Article : Google Scholar : PubMed/NCBI
16	Dawood S, Austin L and Cristofanilli M: Cancer stem cells: Implications for cancer therapy. Oncology (Williston Park). 28:1101–1107, 1110. 2014.PubMed/NCBI
17	Wang T, Shigdar S, Gantier MP, Hou Y, Wang L, Li Y, Shamaileh HA, Yin W, Zhou SF, Zhao X and Duan W: Cancer stem cell targeted therapy: Progress amid controversies. Oncotarget. 6:44191–44206. 2015.PubMed/NCBI
18	Snyder V, Reed-Newman TC, Arnold L, Thomas SM and Anant S: Cancer stem cell metabolism and potential therapeutic targets. Front Oncol. 8:2032018. View Article : Google Scholar : PubMed/NCBI
19	Liu KJ, Wang CC, Chen LT, Cheng AL, Lin DT, Wu YC, Yu WL, Hung YM, Yang HY, Juang SH, et al: Generation of carcinoembryonic antigen (CEA)-specific T-cell responses in HLA-A0201 and HLA-A2402 late-stage colorectal cancer patients after vaccination with dendritic cells loaded with CEA peptides. Clin Cancer Res. 10:2645–2651. 2004. View Article : Google Scholar : PubMed/NCBI
20	Hasegawa H, Mori M, Haraguchi M, Ueo H, Sugimachi K and Akiyoshi T: Expression spectrum of melanoma antigen-encoding gene family members in colorectal carcinoma. Arch Pathol Lab Med. 122:551–554. 1998.PubMed/NCBI
21	Park DI, Kang MS, Oh SJ, Kim HJ, Cho YK, Sohn CI, Jeon WK, Kim BI, Han WK, Kim H, et al: HER-2/neu overexpression is an independent prognostic factor in colorectal cancer. Int J Colorectal Dis. 22:491–497. 2007. View Article : Google Scholar : PubMed/NCBI
22	Chen Q, Cui XX, Liang PF, Dou JX, Liu ZY and Sun WW: Immunotherapy with dendritic cells and cytokine-induced killer cells for MDA-MB-231 breast cancer stem cells in nude mice. Am J Transl Res. 8:2947–2955. 2016.PubMed/NCBI
23	Dashti A, Ebrahimi M, Hadjati J, Memarnejadian A and Moazzeni SM: Dendritic cell based immunotherapy using tumor stem cells mediates potent antitumor immune responses. Cancer Lett. 374:175–185. 2016. View Article : Google Scholar : PubMed/NCBI
24	Jachetti E, Mazzoleni S, Grioni M, Ricupito A, Brambillasca C, Generoso L, Calcinotto A, Freschi M, Mondino A, Galli R and Bellone M: Prostate cancer stem cells are targets of both innate and adaptive immunity and elicit tumor-specific immune responses. Oncoimmunology. 2:e245202013. View Article : Google Scholar : PubMed/NCBI
25	Zhang XF, Weng DS, Pan K, Zhou ZQ, Pan QZ, Zhao JJ, Tang Y, Jiang SS, Chen CL, Li YQ, et al: Dendritic-cell-based immunotherapy evokes potent anti-tumor immune responses in CD105+ human renal cancer stem cells. Mol Carcinog. 56:2499–2511. 2017. View Article : Google Scholar : PubMed/NCBI
26	Sun JC, Pan K, Chen MS, Wang QJ, Wang H, Ma HQ, Li YQ, Liang XT, Li JJ, Zhao JJ, et al: Dendritic cells-mediated CTLs targeting hepatocellular carcinoma stem cells. Cancer Biol Ther. 10:368–375. 2010. View Article : Google Scholar : PubMed/NCBI
27	Li Q, Lu L, Tao H, Xue C, Teitz-Tennenbaum S, Owen JH, Moyer JS, Prince ME, Chang AE and Wicha MS: Generation of a novel dendritic-cell vaccine using melanoma and squamous cancer stem cells. J Vis Exp. e505612014.PubMed/NCBI
28	Gilboa E: DC-based cancer vaccines. J Clin Invest. 117:1195–1203. 2007. View Article : Google Scholar : PubMed/NCBI
29	Fields RC, Shimizu K and Mulé JJ: Murine dendritic cells pulsed with whole tumor lysates mediate potent antitumor immune responses in vitro and in vivo. Proc Natl Acad Sci USA. 95:9482–9487. 1998. View Article : Google Scholar : PubMed/NCBI
30	Boczkowski D, Nair SK, Snyder D and Gilboa E: Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo. J Exp Med. 184:465–472. 1996. View Article : Google Scholar : PubMed/NCBI
31	Nestle FO, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R, Burg G and Schadendorf D: Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med. 4:328–332. 1998. View Article : Google Scholar : PubMed/NCBI
32	Ruben JM, van den Ancker W, Bontkes HJ, Westers TM, Hooijberg E, Ossenkoppele GJ, de Gruijl TD and van de Loosdrecht AA: Apoptotic blebs from leukemic cells as a preferred source of tumor-associated antigen for dendritic cell-based vaccines. Cancer Immunol Immunother. 63:335–345. 2014. View Article : Google Scholar : PubMed/NCBI
33	Rosenberg SA: Cancer vaccines based on the identification of genes encoding cancer regression antigens. Immunol Today. 18:175–182. 1997. View Article : Google Scholar : PubMed/NCBI
34	Kyte JA and Gaudernack G: Immuno-gene therapy of cancer with tumor-mRNA transfected dendritic cells. Cancer Immunol Immunother. 55:1432–1442. 2006. View Article : Google Scholar : PubMed/NCBI
35	Nair SK, Boczkowski D, Morse M, Cumming RI, Lyerly HK and Gilboa E: Induction of primary carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocytes in vitro using human dendritic cells transfected with RNA. Nat Biotechnol. 16:364–369. 1998. View Article : Google Scholar : PubMed/NCBI
36	Pan K, Zhao JJ, Wang H, Li JJ, Liang XT, Sun JC, Chen YB, Ma HQ, Liu Q and Xia JC: Comparative analysis of cytotoxic T lymphocyte response induced by dendritic cells loaded with hepatocellular carcinoma-derived RNA or cell lysate. Int J Biol Sci. 6:639–648. 2010. View Article : Google Scholar : PubMed/NCBI
37	Song Z, Guo C, Li Y, Tan B, Fan L and Xiao J: Enhanced antitumor effects of a dendritic cell vaccine transfected with gastric cancer cell total RNA carrying the 4-1BBL gene in vitro. Exp Ther Med. 3:319–323. 2012. View Article : Google Scholar : PubMed/NCBI
38	Van Tendeloo VF, Ponsaerts P, Lardon F, Nijs G, Lenjou M, Van Broeckhoven C, Van Bockstaele DR and Berneman ZN: Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells: Superiority to lipofection and passive pulsing of mRNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cells. Blood. 98:49–56. 2001. View Article : Google Scholar : PubMed/NCBI
39	Qui P, Ziegelhoffer P, Sun J and Yang NS: Gene gun delivery of mRNA in situ results in efficient transgene expression and genetic immunization. Gene Ther. 3:262–268. 1996.PubMed/NCBI
40	Lutz MB, Kukutsch N, Ogilvie AL, Rössner S, Koch F, Romani N and Schuler G: An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods. 223:77–92. 1999. View Article : Google Scholar : PubMed/NCBI
41	Schnurr M, Galambos P, Scholz C, Then F, Dauer M, Endres S and Eigler A: Tumor cell lysate-pulsed human dendritic cells induce a T-cell response against pancreatic carcinoma cells: An in vitro model for the assessment of tumor vaccines. Cancer Res. 61:6445–6450. 2001.PubMed/NCBI
42	Jin L, Hope KJ, Zhai Q, Smadja-Joffe F and Dick JE: Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med. 12:1167–1174. 2006. View Article : Google Scholar : PubMed/NCBI
43	Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, Hoey T, Gurney A, Huang EH, Simeone DM, et al: Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA. 104:10158–10163. 2007. View Article : Google Scholar : PubMed/NCBI
44	Du L, Wang H, He L, Zhang J, Ni B, Wang X, Jin H, Cahuzac N, Mehrpour M, Lu Y and Chen Q: CD44 is of functional importance for colorectal cancer stem cells. Clin Cancer Res. 14:6751–6760. 2008. View Article : Google Scholar : PubMed/NCBI
45	Janikashvili N, Larmonier N and Katsanis E: Personalized dendritic cell-based tumor immunotherapy. Immunotherapy. 2:57–68. 2010. View Article : Google Scholar : PubMed/NCBI
46	Aarntzen EH, Figdor CG, Adema GJ, Punt CJ and de Vries IJ: Dendritic cell vaccination and immune monitoring. Cancer Immunol Immunother. 57:1559–1568. 2008. View Article : Google Scholar : PubMed/NCBI
47	Nestle FO, Farkas A and Conrad C: Dendritic-cell-based therapeutic vaccination against cancer. Curr Opin Immunol. 17:163–169. 2005. View Article : Google Scholar : PubMed/NCBI
48	Tuyaerts S, Aerts JL, Corthals J, Neyns B, Heirman C, Breckpot K, Thielemans K and Bonehill A: Current approaches in dendritic cell generation and future implications for cancer immunotherapy. Cancer Immunol Immunother. 56:1513–1537. 2007. View Article : Google Scholar : PubMed/NCBI
49	Kokhaei P, Choudhury A, Mahdian R, Lundin J, Moshfegh A, Osterborg A and Mellstedt H: Apoptotic tumor cells are superior to tumor cell lysate, and tumor cell RNA in induction of autologous T cell response in B-CLL. Leukemia. 18:1810–1815. 2004. View Article : Google Scholar : PubMed/NCBI
50	Junking M, Grainok J, Thepmalee C, Wongkham S and Yenchitsomanus PT: Enhanced cytotoxic activity of effector T-cells against cholangiocarcinoma by dendritic cells pulsed with pooled mRNA. Tumour Biol. 39:10104283177333672017. View Article : Google Scholar : PubMed/NCBI
51	Tyagi RK, Mangal S, Garg N and Sharma PK: RNA-based immunotherapy of cancer: Role and therapeutic implications of dendritic cells. Expert Rev Anticancer Ther. 9:97–114. 2009. View Article : Google Scholar : PubMed/NCBI