The immunostimulatory effects of retinoblastoma cell supernatant on dendritic cells

Abstract

Dendritic cells (DCs) are crucial for the induction and maintenance of tumor-specific immune responses. Studies have shown that tumor-associated DCs are immunosuppressed in some human tumors. However, phenotype and function of DCs in retinoblastoma (RB) remain unclear. RB cell supernatant (RBcs) was used to treat DCs in vitro to explore the effect of RB cells on DCs. DCs were generated from peripheral blood mononuclear cells of healthy donors. On day 5 of culture, DCs were treated with RBcs for 24 h, and then purified using magnetic beads. The maturation of DCs was induced by TNF-α or LPS. After treatment with RBcs, expression of co-stimulatory molecules CD80 and CD86 was elevated in DCs, accompanied by increased production of IL-12p70, TNF-α, IL-6, IL-1β, and IL-8 but decreased production of IL-10. RBcs neither inhibited DC maturation nor promoted DC apoptosis. Moreover, RBcs-exposed DCs stimulated allogenetic T cell proliferation and T cell-derived cytokine production. These results indicate that RBcs can improve DCs’ antigen presenting function and capability to activate T cells, suggesting that RB cells may have an immunostimulatory effect on DCs, and Dcbased immunotherapy may be adopted in the treatment of RB.

Keywords

retinoblastoma / dendritic cell / anti-tumor immunity / immunotherapy

References

[1] Ataera H, Hyde E, Price KM, Stoitzner P, Ronchese F (2011) Murine melanoma-infiltrating dendritic cells are defective in antigen presenting function regardless of the presence of CD4CD25 regulatory T cells. PLoS One6: e17515

[2] Beckebaum S, Zhang X, Chen X, Yu Z, Frilling A, Dworacki G, Grosse-Wilde H, Broelsch CE, Gerken G, Cicinnati VR (2004) Increased levels of interleukin-10 in serum from patients with hepatocellular carcinoma correlate with profound numerical deficiencies and immature phenotype of circulating dendritic cell subsets. Clin Cancer Res10: 7260-7269

[3] Bharadwaj U, Li M, Zhang R, Chen C, Yao Q(2007) Elevated interleukin-6 and G-CSF in human pancreatic cancer cell conditioned medium suppress dendritic cell differentiation and activation. Cancer Res67: 5479-5488

[4] Carreno BM, Collins M(2002) The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses. Annu Rev Immunol20: 29-53

[5] Chaux P, Favre N, Martin M, Martin F (1997) Tumor-infiltrating dendritic cells are defective in their antigen-presenting function and inducible B7 expression in rats. Int J Cancer72: 619-624

[6] Collins M, Ling V, Carreno BM (2005) The B7 family of immuneregulatory ligands. Genome Biol6: 223

[7] Colombo MP, Trinchieri G(2002) Interleukin-12 in anti-tumor immunity and immunotherapy. Cytokine Growth Factor Rev13: 155-168

[8] Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez M, Poulot V, Rabbe N, Laurans L, Tartour E, de Chaisemartin L (2008) Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol26: 4410-4417

[9] Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP(1996) Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med2: 1096-1103

[10] Gottfried E, Kreutz M, Mackensen A (2008) Tumor-induced modulation of dendritic cell function. Cytokine Growth Factor Rev19: 65-77

[11] Houston SK, Murray TG, Wolfe SQ, Fernandes CE(2011) Current update on retinoblastoma. Int Ophthalmol Clin51: 77-91

[12] Iwamoto M, Shinohara H, Miyamoto A, Okuzawa M, Mabuchi H, Nohara T, Gon G, Toyoda M, Tanigawa N (2003) Prognostic value of tumor-infiltrating dendritic cells expressing CD83 in human breast carcinomas. Int J Cancer104: 92-97

[13] Kanto T, Kalinski P, Hunter OC, Lotze MT, Amoscato AA(2001) Ceramide mediates tumor-induced dendritic cell apoptosis. J Immunol167: 3773-3784

[14] Khetan V, Mathur G, Kumar SK, Gopal L (2013) Late recurrence of tumor necessitating enucleation in an adult onset retinoblastoma. Ophthalmic Genet34: 87-89

[15] Kiertscher SM, Luo J, Dubinett SM, Roth MD(2000) Tumors promote altered maturation and early apoptosis of monocytederived dendritic cells. J Immunol164: 1269-1276

[16] Kubin M, Kamoun M, Trinchieri G(1994) Interleukin 12 synergizes with B7/CD28 interaction in inducing efficient proliferation and cytokine production of human T cells. J Exp Med180: 211-222

[17] Ladanyi A, Kiss J, Somlai B, Gilde K, Fejos Z, Mohos A, Gaudi I, Timar J(2007) Density of DC-LAMP(+) mature dendritic cells in combination with activated T lymphocytes infiltrating primary cutaneous melanoma is a strong independent prognostic factor. Cancer Immunol Immunother56: 1459-1469

[18] Lim DS, Kim JH, Lee DS, Yoon CH, Bae YS(2007) DC immunotherapy is highly effective for the inhibition of tumor metastasis or recurrence, although it is not efficient for the eradication of established solid tumors. Cancer Immunol Immunother56: 1817-1829

[19] Lippitz BE(2013) Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol14: e218-e228

[20] Loza MJ, Perussia B(2001) Final steps of natural killer cell maturation: a model for type 1 type 2 differentiation? Nat Immunol2: 917-924

[21] Lundqvist A, Nagata T, Kiessling R, Pisa P(2002) Mature dendritic cells are protected from Fas/CD95-mediated apoptosis by upregulation of Bcl-X(L). Cancer Immunol Immunother51: 139-144

[22] Ma J, Usui Y, Takeuchi M, Okunuki Y, Kezuka T, Zhang L, Mizota A, Goto H(2010) Human uveal melanoma cells inhibit the immunostimulatory function of dendritic cells. Exp Eye Res91: 491-499

[23] Merchant TE, Gould CJ, Wilson MW, Hilton NE, Rodriguez-Galindo C, Haik BG (2004) Episcleral plaque brachytherapy for retinoblastoma. Pediatr Blood Cancer43: 134-139

[24] Michielsen AJ, Hogan AE, Marry J, Tosetto M, Cox F, Hyland JM, Sheahan KD, O’Donoghue DP, Mulcahy HE, Ryan EJ (2011) Tumour tissue microenvironment can inhibit dendritic cell maturation in colorectal cancer. PLoS One6: e27944

[25] Movassagh M, Spatz A, Davoust J, Lebecque S, Romero P, Pittet M, Rimoldi D, Lienard D, Gugerli O, Ferradini L (2004) Selective accumulation of mature DC-Lamp+ dendritic cells in tumor sites is associated with efficient T-cell-mediated antitumor response and control of metastatic dissemination in melanoma. Cancer Res64: 2192-2198

[26] Nakakubo Y, Miyamoto M, Cho Y, Hida Y, Oshikiri T, Suzuoki M, Hiraoka K, Itoh T, Kondo S, Katoh H(2003) Clinical significance of immune cell infiltration within gallbladder cancer. Br J Cancer89: 1736-1742

[27] Preynat-Seauve O, Schuler P, Contassot E, Beermann F, Huard B, French LE (2006) Tumor-infiltrating dendritic cells are potent antigen-presenting cells able to activate T cells and mediate tumor rejection. J Immunol176: 61-67

[28] Preynat-Seauve O, Contassot E, Schuler P, French LE, Huard B (2007) Melanoma-infiltrating dendritic cells induce protective antitumor responses mediated by Tcells. Melanoma Res17: 169-176

[29] Sandel MH, Dadabayev AR, Menon AG, Morreau H, Melief CJ, Offringa R, van der Burg SH, Janssen-van Rhijn CM, Ensink NG, Tollenaar RA (2005) Prognostic value of tumor-infiltrating dendritic cells in colorectal cancer: role of maturation status and intratumoral localization. Clin Cancer Res11: 2576-2582

[30] Schueler AO, Jurklies C, Heimann H, Wieland R, Havers W, Bornfeld N(2003) Thermochemotherapy in hereditary retinoblastoma. Br J Ophthalmol87: 90-95

[31] Sombroek CC, Stam AG, Masterson AJ, Lougheed SM, Schakel MJ, Meijer CJ, Pinedo HM, van den Eertwegh AJ, Scheper RJ, de Gruijl TD (2002) Prostanoids play a major role in the primary tumor-induced inhibition of dendritic cell differentiation. J Immunol168: 4333-4343

[32] Stoitzner P, Green LK, Jung JY, Price KM, Atarea H, Kivell B, Ronchese F (2008) Inefficient presentation of tumor-derived antigen by tumor-infiltrating dendritic cells. Cancer Immunol Immunother57: 1665-1673

[33] Treilleux I, Blay JY, Bendriss-Vermare N, Ray-Coquard I, Bachelot T, Guastalla JP, Bremond A, Goddard S, Pin JJ, Barthelemy-Dubois C (2004) Dendritic cell infiltration and prognosis of early stage breast cancer. Clin Cancer Res10: 7466-7474

[34] Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, Bhattacharya R, Gabrilovich D, Heller R, Coppola D (2004) Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med10: 48-54

[35] Zou W (2005) Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer5: 263-274

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2014 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.