Potential function of CTLA‑4 in the tumourigenic capacity of melanoma stem cells

Zhang,Bingyu; Dang,Jianzhong; Ba,Diandian; Wang,Cencen; Han,Juan; Zheng,Fang

doi:10.3892/ol.2018.9354

Potential function of CTLA‑4 in the tumourigenic capacity of melanoma stem cells

Authors:
- Bingyu Zhang
- Jianzhong Dang
- Diandian Ba
- Cencen Wang
- Juan Han
- Fang Zheng
View Affiliations

Affiliations: Department of Paediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China, Department of Geriatrics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
Published online on: August 23, 2018 https://doi.org/10.3892/ol.2018.9354
Pages: 6163-6170

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

Extensive clinical evidence supports that cytotoxic T lymphocyte antigen‑4 (CTLA‑4) is expressed in a variety of human malignant tumour cells in addition to T cells. In certain types of cancer, the overexpression of CTLA‑4 is associated with poor patient prognosis. However, few studies have demonstrated the effects of tumour‑intrinsic CTLA‑4 in cancer stem cells, including melanoma stem cells (MSCs). In the present study, it was demonstrated that melanoma cell‑intrinsic CTLA‑4 induced tumour cell proliferation in vitro and suppressed tumour cell apoptosis. Furthermore, CTLA‑4 was expressed in aldehyde dehydrogenase (ALDH)+ MSCs. CTLA‑4 inhibited MSCs proliferation in vitro by blocking antibodies and significantly downregulated ALDH1A1, ALDH1A3 and ALDH2 mRNA expression (P<0.01). Functionally, blocking CTLA‑4 in melanoma cell lines suppressed the properties of stem‑like cells, including ALDH activity and significantly suppressed the ability of these cells to form spheres in vitro (P<0.05). In addition, the blocking of CTLA‑4 in melanoma cells suppressed the properties of stem‑like cells in vivo, including the capacity for tumourigenesis. The presence of residual ALDH+ MSCs within the tumour was observed, and the blocking CTLA‑4 significantly decreased the number of residual ALDH+ MSCs in vivo (P<0.01). Altogether, these results indicate the identification of a novel mechanism underlying melanoma progression in the present study and that CTLA‑4‑targeted therapy may benefit candidate CTLA‑4‑targeted therapy by improving the long‑term outcome for patients with advanced stages of melanoma.

View Figures

View References

1	Gray-Schopfer V, Wellbrock C and Marais R: Melanoma biology and new targeted therapy. Nature. 445:851–857. 2007. View Article : Google Scholar : PubMed/NCBI
2	Murphy GF, Wilson BJ, Girouard SD, Frank NY and Frank MH: Stem cells and targeted approaches to melanoma cure. Mol Aspects Med. 39:33–49. 2014. View Article : Google Scholar : PubMed/NCBI
3	Hirohashi Y, Torigoe T, Tsukahara T, Kanaseki T, Kochin V and Sato N: Immune responses to human cancer stem-like cells/cancer-initiating cells. Cancer Sci. 107:12–17. 2016. View Article : Google Scholar : PubMed/NCBI
4	Brunner MC, Chambers CA, Chan FK, Hanke J, Winoto A and Allison JP: CTLA-4-mediated inhibition of early events of T cell proliferation. J Immunol. 162:5813–5820. 1999.PubMed/NCBI
5	Wu L, Yun Z, Tagawa T, Rey-McIntyre K and de Perrot M: CTLA-4 blockade expands infiltrating T cells and inhibits cancer cell repopulation during the intervals of chemotherapy in murine mesothelioma. Mol Cancer Ther. 11:1809–1819. 2012. View Article : Google Scholar : PubMed/NCBI
6	Whiteside TL: Regulatory T cell subsets in human cancer: Are they regulating for or against tumor progression? Cancer Immunol Immunother:. 63:67–72. 2014. View Article : Google Scholar : PubMed/NCBI
7	Lindau D, Gielen P, Kroesen M, Wesseling P and Adema GJ: The immunosuppressive tumour network: Myeloid-derived suppressor cells, regulatory T cells and natural killer T cells. Immunology. 138:105–115. 2013. View Article : Google Scholar : PubMed/NCBI
8	Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 363:711–723. 2010. View Article : Google Scholar : PubMed/NCBI
9	Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, et al: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 364:2517–2526. 2011. View Article : Google Scholar : PubMed/NCBI
10	Suwalska K, Pawlak E, Karabon L, Tomkiewicz A, Dobosz T, Urbaniak-Kujda D, Kuliczkowski K, Wolowiec D, Jedynak A and Frydecka I: Association studies of CTLA-4, CD28 and ICOS gene polymorphisms with B-cell chronic lymphocytic leukemia in the Polish population. Hum Immunol. 69:193–201. 2008. View Article : Google Scholar : PubMed/NCBI
11	Monne M, Piras G, Palmas A, Arru L, Murineddu M, Latte G, Noli A and Gabbas A: Cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene polymorphism and susceptibility to non-Hodgkin's lymphoma. Am J Hematol. 76:14–18. 2004. View Article : Google Scholar : PubMed/NCBI
12	Yu H, Yang J, Jiao S, Li Y, Zhang W and Wang J: Cytotoxic T lymphocyte antigen 4 expression in human breast cancer: Implications for prognosis. Cancer Immunol Immunother. 64:853–860. 2015. View Article : Google Scholar : PubMed/NCBI
13	Khaghanzadeh N, Erfani N, Ghayumi MA and Ghaderi A: CTLA4 gene variations and haplotypes in patients with lung cancer. Cancer Genet Cytogenet. 196:171–174. 2010. View Article : Google Scholar : PubMed/NCBI
14	Laurent S, Queirolo P, Boero S, Salvi S, Piccioli P, Boccardo S, Minghelli S, Morabito A, Fontana V, Pietra G, et al: The engagement of CTLA-4 on primary melanoma cell lines induces antibody-dependent cellular cytotoxicity and TNF-alpha production. J Transl Med. 11:1082013. View Article : Google Scholar : PubMed/NCBI
15	Hadinia A, Hossieni SV, Erfani N, Saberi-Firozi M, Fattahi MJ and Ghaderi A: CTLA-4 gene promoter and exon 1 polymorphisms in Iranian patients with gastric and colorectal cancers. J Gastroenterol Hepatol. 22:2283–2287. 2007. View Article : Google Scholar : PubMed/NCBI
16	Pawlak E, Karabon L, Wlodarska-Polinska I, Jedynak A, Jonkisz A, Tomkiewicz A, Kornafel J, Stepien M, Ignatowicz A, Lebioda A, et al: Influence of CTLA-4/CD28/ICOS gene polymorphisms on the susceptibility to cervical squamous cell carcinoma and stage of differentiation in the Polish population. Hum Immunol. 71:195–200. 2010. View Article : Google Scholar : PubMed/NCBI
17	Zhang XF, Pan K, Weng DS, Chen CL, Wang QJ, Zhao JJ, Pan QZ, Liu Q, Jiang SS, Li YQ, et al: Cytotoxic T lymphocyte antigen-4 expression in esophageal carcinoma: Implications for prognosis. Oncotarget. 7:26670–26679. 2016.PubMed/NCBI
18	Contardi E, Palmisano GL, Tazzari PL, Martelli AM, Falà F, Fabbi M, Kato T, Lucarelli E, Donati D, Polito L, et al: CTLA-4 is constitutively expressed on tumor cells and can trigger apoptosis upon ligand interaction. Int J Cancer. 117:538–550. 2005. View Article : Google Scholar : PubMed/NCBI
19	Dai F, Zhang F, Sun D, Zhang ZH, Dong SW and Xu JZ: CTLA4 enhances the osteogenic differentiation of allogeneic human mesenchymal stem cells in a model of immune activation. Braz J Med Biol Res. 48:629–636. 2015. View Article : Google Scholar : PubMed/NCBI
20	Duarte S, Momier D, Baqué P, Casanova V, Loubat A, Samson M, Guigonis JM, Staccini P, Saint-Paul MC, De Lima MP, et al: Preventive cancer stem cell-based vaccination reduces liver metastasis development in a rat colon carcinoma syngeneic model. Stem Cells. 31:423–432. 2013. View Article : Google Scholar : PubMed/NCBI
21	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C (T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
22	Ning N, Pan Q, Zheng F, Teitz-Tennenbaum S, Egenti M, Yet J, Li M, Ginestier C, Wicha MS, Moyer JS, et al: Cancer stem cell vaccination confers significant antitumor immunity. Cancer Res. 72:1853–1864. 2012. View Article : Google Scholar : PubMed/NCBI
23	Choi AR, Park JR, Kim RJ, Kim SR, Cho SD, Jung JY and Nam JS: Inhibition of Wnt1 expression reduces the enrichment of cancer stem cells in a mouse model of breast cancer. Biochem Biophys Res Commun. 425:436–442. 2012. View Article : Google Scholar : PubMed/NCBI
24	Li F, Guo Z, Yu H, Zhang X, Si T, Liu C, Yang X and Qi L: Anti-tumor immunological response induced by cryoablation and anti-CTLA-4 antibody in an in vivo RM-1 cell prostate cancer murine model. Neoplasma. 61:659–671. 2014. View Article : Google Scholar : PubMed/NCBI
25	Shinoyama M, Ideguchi M, Hayashi H, Doi D, Hashimoto N, Suzuki M and Takahashi J: Cytotoxic T lymphocyte antigen 4 immunogloblin promotes neuronal differentiation in the grafts of embryonic stem cell-derived neural precursor cells. Neuroscience. 202:484–491. 2012. View Article : Google Scholar : PubMed/NCBI
26	Luo Y, Dallaglio K, Chen Y, Robinson WA, Robinson SE, McCarter MD, Wang J, Gonzalez R, Thompson DC, Norris DA, et al: ALDH1A isozymes are markers of human melanoma stem cells and potential therapeutic targets. Stem Cells. 30:2100–2113. 2012. View Article : Google Scholar : PubMed/NCBI
27	Topalian SL, Taube JM, Anders RA and Pardoll DM: Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer. 16:275–287. 2016. View Article : Google Scholar : PubMed/NCBI
28	Callahan MK, Postow MA and Wolchok JD: Immunomodulatory therapy for melanoma: Ipilimumab and beyond. Clin Dermatol. 31:191–199. 2013. View Article : Google Scholar : PubMed/NCBI
29	Ji RR, Chasalow SD, Wang L, Hamid O, Schmidt H, Cogswell J, Alaparthy S, Berman D, Jure-Kunkel M, Siemers NO, et al: An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol Immunother. 61:1019–1031. 2012. View Article : Google Scholar : PubMed/NCBI