Abstract
Prostate cancer is the most common cancer in men in the United States, and second in cancer-induced mortality. It is likely that tumour-induced immunosuppression is one of the reasons for low treatment efficacy in patients with advanced prostate cancer. It has been recently demonstrated that prostate cancer tissue is almost devoid of dendritic cells (DC), the major antigen-presenting cells responsible for the induction of specific antitumour immune responses. In this study, we have tested the hypothesis that prostate cancer induces progressive suppression of the DC system. We found that co-incubation of human DC with three prostate cancer cell lines led to the high levels of premature apoptosis of DC, which were significantly higher than in DC cultures co-incubated with normal prostate cells or blood leucocytes. Stimulation of DC for 24 hours with CD40 ligand (CD154), IL-12 or IL-15 prior to their co-incubation with prostate cancer cells resulted in a significant increase in DC survival in the tumour microenvironment. Furthermore, activation of DC with these cytokines was also accompanied by increased expression of the anti-apoptotic protein Bcl-xLin DC, suggesting a possible mechanism involved in DC protection from apoptotic death. In summary, our data demonstrate that prostate cancer induces active elimination of DC in the tumour microenvironment. Stimulation of DC by CD154, IL-12 or IL-15 leads to an increased expression of the anti-apoptotic protein Bcl-xLand increased resistance of DC to prostate cancer-induced apoptosis. These results suggest a new mechanism of tumour escape from immune recognition and demonstrate the cytokine-based approaches which might significantly increase the efficacy of DC-based therapies for cancer. © 2000 Cancer Research Campaign
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References
Akifusa S, Ohguchi M, Koseki T, Nara K, Semba I, Yamato K, Okahashi N, Merino R, Nunez G, Hanada N, Takehara T and Nishihara T (1998) Increase in Bcl-2 level promoted by CD40 ligation correlates with inhibition of B cell apoptosis induced by vacuolar type H(+)-ATPase inhibitor. Experimental Cell Research 238: 82–89
Alam MK, Davison S, Siddiqui N, Norton JD and Murphy JJ (1997) Ectopic expression of Bcl-2, but not Bcl-xL rescues Ramos B cells from Fas-mediated apoptosis. European Journal of Immunology 27: 3485–3491
Arpin C, Dechanet J, Van Kooten C, Merville P, Grouard G, Briere F, Banchereau J and Liu YJ (1995) Generation of memory B cells and plasma cells in vitro. Science 268: 720–722
Avice MN, Demeure CE, Delespesse G, Rubio M, Armant M and Sarfati M (1998) IL-15 promotes IL-12 production by human monocytes via T cell-dependent contact and may contribute to IL-12-mediated IFN-gamma secretion by CD4+ T cells in the absence of TCR ligation. Journal of Immunology 161: 3408–3415
Bander NH, Yao D, Liu H, Chen YT, Steiner M, Zuccaro W and Moy P (1997) MHC class I and II expression in prostate carcinoma and modulation by interferon-alpha and -gamma. Prostate 33: 233–239
Becker Y (1992) Anticancer role of dendritic cells (DC) in human and experimental cancers – a review. Anticancer Research 12: 511–520
Bellone G and Trinchieri G (1994) Dual stimulatory and inhibitory effect of NK cell stimulatory factor/IL-12 on human hematopoiesis. Journal of Immunology 153: 930–937
Bigotti G, Coli A and Castagnola D (1991) Distribution of Langerhans cells and HLA class II molecules in prostatic carcinomas of different histopathological grade. Prostate 19: 73–87
Bjorck P, Banchereau J and Flores-Romo L (1997) CD40 ligation counteracts Fas-induced apoptosis of human dendritic cells. International Immunology 9: 365–372
Bluman EM, Bartynski KJ, Avalos BR and Caligiuri MA (1996) Human natural killer cells produce abundant macrophage inflammatory protein-1 alpha in response to monocyte-derived cytokines. Journal of Clinical Investigation 97: 2722–2727
Bulfone-Paus S, Ungureanu D, Pohl T, Lindner G, Paus R, Ruckert R, Krause H and Kunzendorf U (1997) Interleukin-15 protects from lethal apoptosis in vitro. Nature Medicine 3: 1124–1128
Burchardt T, Burchardt M, Chen MW, Cao Y, de la Taille A, Shabsigh A, Hayek O, Dorai T and Buttyan R (1999) Transdifferentiation of prostate cancer cells to a neuroendocrine cell phenotype in vitro and in vitro. J Urol 162: 1800–1805
Cardillo MR, Petrangeli E, Perracchio L, Salvatori L, Ravenna L and Di Silverio F (2000) Transforming growth factor-beta expression in prostate neoplasia [In Process Citation]. Anal Quant Cytol Histol 22: 1–10
Carson WE, Ross ME, Baiocchi RA, Marien MJ, Boiani N, Grabstein K and Caligiuri MA (1995) Endogenous production of interleukin 15 by activated human monocytes is critical for optimal production of interferon-gamma by natural killer cells in vitro. Journal of Clinical Investigation 96: 2578–2582
Carson WE, Fehniger TA, Haldar S, Eckhert K, Lindemann MJ, Lai CF, Croce CM, Baumann H and Caligiuri MA (1997) A potential role for interleukin-15 in the regulation of human natural killer cell survival. Journal of Clinical Investigation 99: 937–943
Caux C, Massacrier C, Dubois B, Valladeau J, Dezutter-Dambuyant C, Durand I, Schmitt D and Saeland S (1999) Respective involvement of TGF-beta and IL-4 in the development of Langerhans cells and non-Langerhans dendritic cells from CD34+ progenitors. J Leukoc Biol 66: 781–791
Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A and Alber G (1996) Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. Journal of Experimental Medicine 184: 747–752
Chan SH, Perussia B, Gupta JW, Kobayashi M, Pospisil M, Young HA, Wolf SF, Young D, Clark SC and Trinchieri G (1991) Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers. Journal of Experimental Medicine 173: 869–879
Davidson PJT, Troy AJ, Atkinson CH and DNJ H (1997) Characterization of the dendritic cell response to the carcinoma of the prostate. AUA 92nd Annual Meeting, New Orleans 370
Eastham JA and Scardino PT (1998) Radical prostatectomy. In: Campbell's Urology, PC Walsh, AB Retik, ED Vaughan, AJ Wein eds. WB Saunders Company, pp 2547–2564
Esche C, Gambotto A, Satoh Y, Gerein V, Robbins PD, Watkins SC, Lotze MT and Shurin MR (1999a) CD154 inhibits tumor-induced apoptosis in dendritic cells and tumor growth. Eur J Immunol 29: 2148–2155
Esche C, Lokshin A, Shurin GV, Gastman BR, Rabinowich H, Watkins SC, Lotze MT and Shurin MR (1999b) Tumor's other immune targets: dendritic cells [In Process Citation]. J Leukoc Biol 66: 336–344
Grohmann U, Fioretti MC, Bianchi R, Belladonna ML, Ayroldi E, Surace D, Silla S and Puccetti P (1998) Dendritic cells, interleukin 12, and CD4+ lymphocytes in the initiation of class I-restricted reactivity to a tumor/self peptide. Critical Reviews in Immunology 18: 87–98
Healy CG, Simons JW, Carducci MA, DeWeese TL, Bartkowski M, Tong KP and Bolton WE (1998) Impaired expression and function of signal-transducing zeta chains in peripheral T cells and natural killer cells in patients with prostate cancer. Cytometry 32: 109–119
Herr HW (1980) Suppressor cells in immunodepressed bladder and prostate cancer patients. Journal of Urology 123: 635–639
Heufler C, Koch F, Stanzl U, Topar G, Wysocka M, Trinchieri G, Enk A, Steinman RM, Romani N and Schuler G (1996) Interleukin-12 is produced by dendritic cells and mediates T helper 1 development as well as interferon-gamma production by T helper 1 cells. European Journal of Immunology 26: 659–668
Ivshina AV, Zhumagazin Zh D, Zabotina TN, Matveev BP and Kadagidze ZG (1995) [Effect of the spread of the process and treatment on the phenotype of peripheral blood lymphocytes in patients with prostatic cancer]. Urologiia i Nefrologiia, 36–38
Jonuleit H, Wiedemann K, Muller G, Degwert J, Hoppe U, Knop J and Enk AH (1997) Induction of IL-15 messenger RNA and protein in human blood-derived dendritic cells: a role for IL-15 in attraction of T cells. Journal of Immunology 158: 2610–2615
Kelsall BL, Stuber E, Neurath M and Strober W (1996) Interleukin-12 production by dendritic cells. The role of CD40-CD40L interactions in Th1 T-cell responses. Annals of the New York Academy of Sciences 795: 116–126
Kerr JF, Wyllie AH and Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. British Journal of Cancer 26: 239–257
Klotz T, Bloch W, Volberg C, Engelmann U and Addicks K (1998) Selective expression of inducible nitric oxide synthase in human prostate carcinoma. Cancer 82: 1897–1903
Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S, Loudon R, Sherman F, Perussia B and Trinchieri G (1989) Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. Journal of Experimental Medicine 170: 827–845
Kubin M, Kamoun M and Trinchieri G (1994) Interleukin 12 synergizes with B7/CD28 interaction in inducing efficient proliferation and cytokine production of human T cells. Journal of Experimental Medicine 180: 211–222
Landis SH, Murray T, Bolden S and Wingo PA (1999) Cancer statistics, 1999. Ca: a Cancer Journal for Clinicians 49: 8–31
Lorenz HM, Hieronymus T, Grunke M, Manger B and Kalden JR (1997) Differential role for IL-2 and IL-15 in the inhibition of apoptosis in short-term activated human lymphocytes. Scandinavian Journal of Immunology 45: 660–669
Lotze MT (1997) Getting to the source: dendritic cells as therapeutic reagents for the treatment of patients with cancer. Annals of Surgery 226: 1–5
Ludewig B, Graf D, Gelderblom HR, Becker Y, Kroczek RA and Pauli G (1995) Spontaneous apoptosis of dendritic cells is efficiently inhibited by TRAP (CD40-ligand) and TNF-alpha, but strongly enhanced by interleukin-10. Eur J Immunol 25: 1943–1950
Mackey MF, Gunn JR, Maliszewsky C, Kikutani H, Noelle RJ and Barth RJ Jr (1998) Dendritic cells require maturation via CD40 to generate protective antitumor immunity. Journal of Immunology 161: 2094–2098
Nakajima A, Kodama T, Morimoto S, Azuma M, Takeda K, Oshima H, Yoshino S, Yagita H and Okumura K (1998) Antitumor effect of CD40 ligand: elicitation of local and systemic antitumor responses by IL-12 and B7. Journal of Immunology 161: 1901–1907
Ning ZQ, Norton JD, Li J and Murphy JJ (1996) Distinct mechanisms for rescue from apoptosis in Ramos human B cells by signaling through CD40 and interleukin-4 receptor: role for inhibition of an early response gene, Berg36. European Journal of Immunology 26: 2356–2363
Peng X, Remacle JE, Kasran A, Huylebroeck D and Ceuppens JL (1998) IL-12 up-regulates CD40 ligand (CD154) expression on human T cells. Journal of Immunology 160: 1166–1172
Ploemacher RE, van Soest PL, Voorwinden H and Boudewijn A (1993) Interleukin-12 synergizes with interleukin-3 and steel factor to enhance recovery of murine hemopoietic stem cells in liquid culture. Leukemia 7: 1381–1388
Salgaller ML, Lodge PA, McLean JG, Tjoa BA, Loftus DJ, Ragde H, Kenny GM, Rogers M, Boynton AL and Murphy GP (1998a) Report of immune monitoring of prostate cancer patients undergoing T-cell therapy using dendritic cells pulsed with HLA-A2-specific peptides from prostate-specific membrane antigen (PSMA). Prostate 35: 144–151
Salgaller ML, Tjoa BA, Lodge PA, Ragde H, Kenny G, Boynton A and Murphy GP (1998b) Dendritic cell-based immunotherapy of prostate cancer. Critical Reviews in Immunology 18: 109–119
Salup RR, Deng DH and Baar J (1998) Analysis of Fas expression and growth of prostate cancer cells. Proceed. AACR 39: 580–581
Sbih-Lammali F, Clausse B, Ardila-Osorio H, Guerry R, Talbot M, Havouis S, Ferradini L, Bosq J, Tursz T and Busson P (1999) Control of apoptosis in Epstein Barr virus-positive nasopharyngeal carcinoma cells: opposite effects of CD95 and CD40 stimulation. Cancer Research 59: 924–930
Schneider TJ, Grillot D, Foote LC, Nunez GE and Rothstein TL (1997) Bcl-x protects primary B cells against Fas-mediated apoptosis. Journal of Immunology 159: 4834–4839
Sharma N, Luo J, Kirschmann DA, O'Malley Y, Robbins ME, Akporiaye ET, Lubaroff DM, Heidger PM and Hendrix MJ (1999) A novel immunological model for the study of prostate cancer. Cancer Res 59: 2271–2276
Shurin MR (1996) Dendritic cells presenting tumor antigen. Cancer Immunology, Immunotherapy 43: 158–164
Shurin MR (1999) Regulation of dendropoiesis in cancer. Clin Immunol Newsletter 19: 135–139
Shurin MR, Esche C, Lokshin A and Lotze MT (1999) Apoptosis in Dendritic Cells. In: Dendritic Cells: Biology and Clinical Applications, MT Lotze, AW Thomson eds. Academic Press: San Diego, pp 673–692
Stearns ME and Wang M (1998) Antimetastatic and antitumor activities of interleukin 10 in transfected human prostate PC-3 ML clones: Orthotopic growth in severe combined immunodeficient mice. Clin Cancer Res 4: 2257–2263
Stearns ME, Rhim J and Wang M (1999) Interleukin 10 (IL-10) inhibition of primary human prostate cell-induced angiogenesis: IL-10 stimulation of tissue inhibitor of metalloproteinase-1 and inhibition of matrix metalloproteinase (MMP)- 2/MMP-9 secretion. Clin Cancer Res 5: 189–196
Steinman RM and Cohn ZA (1973) Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. Journal of Experimental Medicine 137: 1142–1162
Stene MA, Babajanians M, Bhuta S and Cochran AJ (1988) Quantitative alterations in cutaneous Langerhans cells during the evolution of malignant melanoma of the skin. Journal of Investigative Dermatology 91: 125–128
Strobl H and Knapp W (1999) TGF-betal regulation of dendritic cells. Microbes Infect 1: 1283–1290
Toriyama K, Wen DR, Paul E and Cochran AJ (1993) Variations in the distribution, frequency, and phenotype of Langerhans cells during the evolution of malignant melanoma of the skin. Journal of Investigative Dermatology 100: 269S–273S
Troy A, Davidson P, Atkinson C and Hart D (1998) Phenotypic characterisation of the dendritic cell infiltrate in prostate cancer. Journal of Urology 160: 214–219
Wang M, Liu A, Garcia FU, Rhim JS and Stearns ME (1999) Growth of HPV-18 immortalized human prostatic intraepithelial neoplasia cell lines. Influence of IL-10, follistatin, activin-A, and DHT. Int J Oncol 14: 1185–1195
Wikstrom P, Lindh G, Bergh A and Damber JE (1999) Alterations of transforming growth factor beta1 (TGF-beta1) and TGFbeta receptor expressions with progression in Dunning rat prostatic adenocarcinoma sublines. Urol Res 27: 185–193
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Pirtskhalaishvili, G., Shurin, G., Esche, C. et al. Cytokine-mediated protection of human dendritic cells from prostate cancer-induced apoptosis is regulated by the Bcl-2 family of proteins. Br J Cancer 83, 506–513 (2000). https://doi.org/10.1054/bjoc.2000.1289
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DOI: https://doi.org/10.1054/bjoc.2000.1289
