Identification of an HLA-A2-restricted CD147 epitope that can induce specific CTL cytotoxicity against drug resistant MCF-7/Adr cells

Qu,Chuang; Gao,Shuhui; Shao,Hongwei; Zhang,Wenfeng; Bo,Huabben; Lu,Xin; Chen,Tianjiao; Kou,Jing; Wang,Yue; Chen,Gui  Si; Huang,Shulin; Shen,Han

doi:10.3892/ol.2018.8085

Identification of an HLA-A2-restricted CD147 epitope that can induce specific CTL cytotoxicity against drug resistant MCF-7/Adr cells

Authors:
- Chuang Qu
- Shuhui Gao
- Hongwei Shao
- Wenfeng Zhang
- Huabben Bo
- Xin Lu
- Tianjiao Chen
- Jing Kou
- Yue Wang
- Gui Si Chen
- Shulin Huang
- Han Shen
View Affiliations

Affiliations: Guangdong Province Key Laboratory of Biotechnology Drug Candidates, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, P.R. China
Published online on: February 16, 2018 https://doi.org/10.3892/ol.2018.8085
Pages: 6050-6056

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

Cluster of differentiation (CD)147 is highly expressed in drug-resistant tumor cell lines and is involved in the formation of tumor drug resistance. Therefore, immunotherapy utilizing CD147 epitope peptides is a promising approach for the elimination of drug‑resistant tumor cells. However, like most tumor‑associated antigens (TAAs), CD147 belongs to the autoantigen category, and T cells that recognize high affinity, immunodominant epitopes from autoantigens are deleted though thymic negative selection. Furthermore, wild‑type autoantigen peptides cannot effectively activate and expand T lymphocytes with lower afﬁnity T cell receptors in vivo. However, mutations of TAA peptides have been demonstrated to increase the affinity of major histocompatibility complex molecules and their binding to T cell receptor molecules, leading to activation of T lymphocytes in vitro. In the present study, a high‑affinity point mutation peptide, CD147126‑134L2, was predicted by the human leukocyte antigen (HLA) binding prediction algorithm and its affinity was testified using a T2 binding assay. In addition, when peptide‑specific cytotoxic T lymphocytes (CTLs) were stimulated with dendritic cells loaded with the CD147126‑134L2 peptide under HLA‑A*02:01 restriction, interferon‑γ release and cytotoxicity assays showed that peptide‑specific CTLs effectively cross‑recognized and lysed T2 target cells loaded either with the wild‑type (CD147126‑134) or mutated peptide (CD147126‑134L2). Moreover, the CD147126‑134L2 peptide‑specific CTLs exerted strong cytotoxic activity against drug‑resistant MCF‑7/Adr cells, which express a high level of CD147 and are HLA‑A*02:01‑positive, but not against normal MCF‑7 cells. Thus, this suggests that the wild‑type peptide (CD147126‑134) is naturally presented on HLA‑A*02:01 of CD147‑expressing MCF‑7/Adr cells and is cross‑recognized by CTLs. In conclusion, an HLA‑A*02:01‑restricted CD147‑point mutant epitope peptide was identified that induces CTLs to efficiently lyse drug‑resistant MCF‑7 cells that highly express CD147. Therefore, this immunotherapeutic approach should be explored as a potential treatment for drug-resistant tumors.

View Figures

View References

1	Amiri-Kordestani L, Basseville A, Kurdziel K, Fojo AT and Bates SE: Targeting MDR in breast and lung cancer: Discriminating its potential importance from the failure of drug resistance reversal studies. Drug Resist Updat. 15:50–61. 2012. View Article : Google Scholar : PubMed/NCBI
2	Muramatsu T: Basigin (CD147), a multifunctional transmembrane glycoprotein with various binding partners. J Biochem. 159:481–490. 2016. View Article : Google Scholar : PubMed/NCBI
3	Somno A, Anuchapreeda S, Chruewkamlow N, Pata S, Kasinrerk W and Chiampanichayakul S: Involvement of CD147 on multidrug resistance through the regulation of P-glycoprotein expression in K562/ADR leukemic cell line. Leuk Res Rep. 6:33–38. 2016.PubMed/NCBI
4	Zhou S, Liao L, Chen C, Zeng W, Liu S, Su J, Zhao S, Chen M, Kuang Y, Chen X and Li J: CD147 mediates chemoresistance in breast cancer via ABCG2 by affecting its cellular localization and dimerization. Cancer Lett. 337:285–292. 2013. View Article : Google Scholar : PubMed/NCBI
5	Pan Y, He B, Song G, Bao Q, Tang Z, Tian F and Wang S: CD147 silencing via RNA interference reduces tumor cell invasion, metastasis and increases chemosensitivity in pancreatic cancer cells. Oncol Rep. 27:2003–2009. 2012.PubMed/NCBI
6	Xu BQ, Fu ZG, Meng Y, Wu XQ, Wu B, Xu L, Jiang JL, Li L and Chen ZN: Gemcitabine enhances cell invasion via activating HAb18G/CD147-EGFR-pSTAT3 signaling. Oncotarget. 7:62177–62193. 2016.PubMed/NCBI
7	Kono K, Iinuma H, Akutsu Y, Tanaka H, Hayashi N, Uchikado Y, Noguchi T, Fujii H, Okinaka K, Fukushima R, et al: Multicenter, phase II clinical trial of cancer vaccination for advanced esophageal cancer with three peptides derived from novel cancer-testis antigens. J Transl Med. 10:1412012. View Article : Google Scholar : PubMed/NCBI
8	Suzuki H, Fukuhara M, Yamaura T, Mutoh S, Okabe N, Yaginuma H, Hasegawa T, Yonechi A, Osugi J, Hoshino M, et al: Multiple therapeutic peptide vaccines consisting of combined novel cancer testis antigens and anti-angiogenic peptides for patients with non-small cell lung cancer. J Transl Med. 11:972013. View Article : Google Scholar : PubMed/NCBI
9	Tsang KY, Fantini M, Fernando RI, Palena C, David JM, Hodge JW, Gabitzsch ES, Jones FR and Schlom J: Identification and characterization of enhancer agonist human cytotoxic T-cell epitopes of the human papillomavirus type 16 (HPV16) E6/E7. Vaccine. 35:2605–2611. 2017. View Article : Google Scholar : PubMed/NCBI
10	Colella TA, Bullock TN, Russell LB, Mullins DW, Overwijk WW, Luckey CJ, Pierce RA, Restifo NP and Engelhard VH: Self-tolerance to the murine homologue of a tyrosinase-derived melanoma antigen: Implications for tumor immunotherapy. J Exp Med. 191:1221–1232. 2000. View Article : Google Scholar : PubMed/NCBI
11	Shen H, Shao HW, Chen XH, Wu FL, Wang H, Huang ZL, Shen J, Wang T, Zhang WF and Huang SL: Identification of a novel HLA-A2-restricted mutated Survivin epitope and induction of specific anti-HCC CTLs that could effectively cross-recognize wild-type Survivin antigen. Cancer Immunol Immunother. 62:393–403. 2013. View Article : Google Scholar : PubMed/NCBI
12	Shao H, Lin Y, Wang T, Ou Y, Shen H, Tao C, Wu F, Zhang W, Bo H, Wang H and Huang S: Identification of peptide-specific TCR genes by in vitro peptide stimulation and CDR3 length polymorphism analysis. Cancer Lett. 363:83–91. 2015. View Article : Google Scholar : PubMed/NCBI
13	Wang W, Zou L, Zhou D, Zhou Z, Tang F, Xu Z and Liu X: Overexpression of ubiquitin carboxyl terminal hydrolase-L1 enhances multidrug resistance and invasion/metastasis in breast cancer by activating the MAPK/Erk signaling pathway. Mol Carcinog. 55:1329–1342. 2016. View Article : Google Scholar : PubMed/NCBI
14	Rammensee HG, Bachmann J, Emmerich NP, Bachor OA and Stevanović S: SYFPEITHI: Database for MHC ligands and peptide motifs. Immunogenetics. 50:213–219. 1999. View Article : Google Scholar : PubMed/NCBI
15	Nijman HW, Houbiers JG, Vierboom MP, van der Burg SH, Drijfhout JW, D'Amaro J, Kenemans P, Melief CJ and Kast WM: Identification of peptide sequences that potentially trigger HLA-A2.1-restricted cytotoxic T lymphocytes. Eur J Immunol. 23:1215–1219. 1993. View Article : Google Scholar : PubMed/NCBI
16	Wijdeven RH, Pang B, Assaraf YG and Neefjes J: Old drugs, novel ways out: Drug resistance toward cytotoxic chemotherapeutics. Drug Resist Updat. 28:65–81. 2016. View Article : Google Scholar : PubMed/NCBI
17	Chang A: Chemotherapy, chemoresistance and the changing treatment landscape for NSCLC. Lung Cancer. 71:3–10. 2011. View Article : Google Scholar : PubMed/NCBI
18	Curiel TJ: Immunotherapy: A useful strategy to help combat multidrug resistance. Drug Resist Updat. 15:106–113. 2012. View Article : Google Scholar : PubMed/NCBI
19	Toole BP and Slomiany MG: Hyaluronan, CD44 and Emmprin: Partners in cancer cell chemoresistance. Drug Resist Updat. 11:110–121. 2008. View Article : Google Scholar : PubMed/NCBI
20	Walter M, Simanovich E, Brod V, Lahat N, Bitterman H and Rahat MA: An epitope-specific novel anti-EMMPRIN polyclonal antibody inhibits tumor progression. Oncoimmunology. 5:e10780562015. View Article : Google Scholar : PubMed/NCBI
21	Tourdot S, Scardino A, Saloustrou E, Gross DA, Pascolo S, Cordopatis P, Lemonnier FA and Kosmatopoulos K: A general strategy to enhance immunogenicity of low-affinity HLA-A2.1-associated peptides: Implication in the identification of cryptic tumor epitopes. Eur J Immunol. 30:3411–3421. 2000. View Article : Google Scholar : PubMed/NCBI
22	Engels B, Engelhard VH, Sidney J, Sette A, Binder DC, Liu RB, Kranz DM, Meredith SC, Rowley DA and Schreiber H: Relapse or eradication of cancer is predicted by peptide-major histocompatibility complex affinity. Cancer Cell. 23:516–526. 2013. View Article : Google Scholar : PubMed/NCBI
23	Valmori D, Fonteneau JF, Lizana CM, Gervois N, Liénard D, Rimoldi D, Jongeneel V, Jotereau F, Cerottini JC and Romero P: enhanced generation of specific tumor-reactive ctl in vitro by selected melan-a/mart-1 immunodominant peptide analogues. J Immunol. 160:1750–1758. 1998.PubMed/NCBI
24	Slansky JE, Rattis FM, Boyd LF, Fahmy T, Jaffee EM, Schneck JP, Margulies DH and Pardoll DM: Enhanced antigen-specific antitumor immunity with altered peptide ligands that stabilize the MHC-peptide-TCR complex. Immunity. 13:529–538. 2000. View Article : Google Scholar : PubMed/NCBI