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Cross-Priming of Cytotoxic T Cells Promoted by Apoptosis-Inducing Tumor Cell Reactive Antibodies?

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Abstract

Humanizing xenogenic monoclonal antibodies (MAbs) by genetic engineering has greatly improved their therapeutic utility and efficacy. The chimeric CD20 MAb C2B8 (Rituximab) is a prominent representative of this new generation of therapeutic MAbs and has been proposed as a treatment of choice for recurrent follicular non-Hodgkin's lymphomas. Treatment of CD20+ B cells with MAb C2B8 triggers several cell-damaging actions including complement-mediated lysis (CDL), antibody-dependent cellular cytotoxicity (ADCC), and MAb-induced induction of apoptosis. We provide an overview of the most prominent mechanisms underlying the efficacy of antibody treatment. We introduce our concept of cross-priming of cytotoxic T-cell responses promoted by apoptosis incucing antibodies. Treatment of tumor cells with antibodies that are capable of inducing a proapoptotic signal via their cell surface target structure may not only contribute to their direct killing but also may induce cellular responses against the tumor, which may have a long-lasting protective effect. We report, using the example of C2B8 anti-CD20 treatment of lymphoma cells, that MAb C2B8-induced apoptosis of lymphoma cells not only kills these cells but also promotes uptake and cross-presentation of lymphoma cell-derived peptides by antigen-presenting dendritic cells (DC), induces maturation of DC, and allows the generation of specific CTL.

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REFERENCES

  1. Kohler G, Milstein C: Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495–497, 1975

    Google Scholar 

  2. Glennie MJ, Johnson PWM: Clinical trials of antibody therapy. Immunol Today 21:403–410, 2000

    Google Scholar 

  3. Schroff RW, Foon KA, Beatty SM, Oldham RK, Morgan AC Jr: Human anti-murine immunoglobulin responses in patients receiving monoclonal antibody therapy. Cancer Res 45:879–885, 1985

    Google Scholar 

  4. Shawler DL, Bartholomew RM, Smith LM, Dillman RO: Human immune response to multiple injections of murine monoclonal igG. J Immunol 135:1530–1535, 1985

    Google Scholar 

  5. Clark M: Antibody humanization: A case of the “emperors new clothes.” Immunol Today 21:397–402, 2000

    Google Scholar 

  6. Clynes RA, Towers TL, Presta LG, Ravetch JV: Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med 6:373–374, 2000

    Google Scholar 

  7. Rowan W, Tite J, Topley P, Brett SJ: Cross-linking of the CAMPATH-1H antigen (CD52) mediates growth inhibition in human B-and T-lymphoma cell lines, and subsequent emergence of CD52 deficient cells. Immunologgy 95:427–436, 1998

    Google Scholar 

  8. Lugering A, Schmidt M, Lugering N, Paueks HG, Domschke W, Kucharzik T: Infliximab induces apoptosis in monocytes from patients with chronic active Chron' disease by using a caspasedependent pathway. Gastroenterology 121:1145–1157, 2001

    Google Scholar 

  9. Masui H, Kawamoto T, Sato JD, Wolf B, Sato G, Mendelsohn J: Growth inhibition of human tumor cells in athymic mice by antiepidermal growth factor monoclonal antibodies. Cancer Res 44:1002–1007, 1984

    Google Scholar 

  10. Drebin JA, Link VC, Stern DF, Weinberg RA, Greene MI: Down-modulation of an oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies. Cell 41: 697–706, 1985

    Google Scholar 

  11. Shan D, Ledbetter JA, Press OW: Apoptosis of malignant human B cells by ligation of CD20 with monoclonal antibodies. Blood 91:1644–1652, 1998

    Google Scholar 

  12. Cragg MS, French RR, Glennie MJ: Signaling antibodies in cancer therapy. Curr Opin Immunol 11:541–547, 1999

    Google Scholar 

  13. Shan D, Ledbetter JA, Press OW: Signaling events involved in anti-CD20-induced apoptosis of malignant human B cells. Cancer Immunol immunother 48:673–683, 2000

    Google Scholar 

  14. Mc Laughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White, CA, Cabanillas F, Jain, V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825–2833, 1998

    Google Scholar 

  15. Maloney DG, Grillo-Lopez AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, Janakiraman N, Foon KA, Liles TM, Dallaire BK, Wey I, Royston K, Davis T, Levy R: IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin' lymphoma. Blood 90:2188–2195, 1997

    Google Scholar 

  16. Maloney DG: Advances in immunotherapy of hematologic malignancies. Curr Opin Haematol 5:237–243, 1998

    Google Scholar 

  17. Mc Laughlin P, Cabanillas F, Grillo-Lopez AJ, Link BK, Levy R, Czuczman M, Heyman MR, Williams M, Jain V, Bence-Bruckler I, Ho AD, Lister J, Wey K, Dallaire BK, Shen D: Final report on a phase III pivotal trial in patients with relapsed low-grade or follicular lymphoma. Blood 90a:abstr,suppl 1, 1996

  18. Coiffier B, Haioun C, Ketterer N, Engert A, Tilly H, Ma D, Johnson P, Lister A, Feurig-Buske M, Radford JA, Capdeville R, Diel V, Reyes F: Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: A multicenter phase II study. Blood 92:1927–1932, 1998

    Google Scholar 

  19. Hainsworth JD, Burris III HH, Morrissey LH, Litchy S, Scullin Jr DC, Bearden JD, Richards P, Greco, FA: Rituximab monoclonal antibody as initial systemic therapy for patients with low-grade non-Hodgkin lymphoma. Blood 95:3052–3056, 2000

    Google Scholar 

  20. Bevan MJ,: Cross-priming for a secondary cytotoxic response to minor H antigens with H-2 congenic cells which do not cross-react in the cytotoxic assay. J Exp Med 143:1283–1288, 1976

    Google Scholar 

  21. Albert ML, Sauter B, Bhardwaj N: Dendritic cells acquire antigen from apoptotic cells and induce class-I restricted CTLs. Nature 392:86–89, 1998

    Google Scholar 

  22. Norbury CC, Hewlett LJ, Shastri N, Watts C: Class-I MHC presentation of exogenous soluble antigen via macropinocytosis in bone marrow macrophages. Immunity 3:783–791, 1995

    Google Scholar 

  23. Norbury CC, Chambers BJ, Prescott AR, Ljunggren HG, Watts C: Constitutive macropinocytosis allows TAP-dependent presentation of exogenous antigen on class-I MHC molecules by bone marrow derived dendritic cells. Eur J Immunol. 27:280–288, 1997

    Google Scholar 

  24. Bellone M, Iezzi G, Rovere P, Galati G, Ronchetti A, Protti MP, Davoust J, Rugarli C, Manfredi AA: Processing of engulfed apoptotic bodies yields T-cell epitopes. J Immunol 159:5391–5399, 1997

    Google Scholar 

  25. Ronchetti A, Giandomenica I, Crosti MC, Garancini MP, Protti MP, Bellone M: Role of antigen presenting cells in cross-priming of cytotoxic T-lymphocytes by apoptotic cells. J Leukoc Biol 66:247–251, 1999

    Google Scholar 

  26. Heath WR, Carbone FR: Cross-presentation, dendritic cells, tolerance and immunity. Annu Rev Immunol 19:47–64, 2001

    Google Scholar 

  27. Suto R, Srivastava PK: A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Science 269: 1585–1588, 1995

    Google Scholar 

  28. Wolfers J, Lotzier A, Raposo G, Regnault A, Thery C, Masurier C, Flament C, Pouzieux S, Faure F, Tursz T, Angevin E, Amigorena S, Zitvogel L: Tumor derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat Med 7:297–303, 2001

    Google Scholar 

  29. Regnault A, Lankar D, Lacabanne V, Rodriguez A, Thery C, Rescigno M, Saito T, Verbeek S, Bonnerot C, Ricciardi-Castagnoli P, Amigorena S: Fegamma receptor mediated induction of dendritic cell maturation and major histocompatibility complex class-I restricted antigen presentation after immune complex internalisation. J Exp Med 189:371–380, 1999

    Google Scholar 

  30. Russo V, Tanzarella S, Dalerba P, Rigatti D, Rovere P, Villa A, Bordignon C, Traversari C: Dendritic cells acquire the MAGE-3 human tumor antigen from apoptotic cells and induce class-I restricted T-cell response. Proc Natl Acad Sci USA 97:2185–2190, 2000

    Google Scholar 

  31. Yrlid BU, Wick MJ: Salmonella-induced apoptosis of infected macrophages results in presentation of a bacteria-encoded antigen after uptake by bystander dendritic cells. J Exp Med 191:613–621, 2000

    Google Scholar 

  32. Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A, Alber G: 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. J Exp Med 184:747–752, 1996

    Google Scholar 

  33. Sauter B, Albert ML, Francisco LM, Larrson M, Somersan S, Bhardwaj N: Consequences of cell death: Exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells induces the maturation of immunostimulatory dendritic cells. J Exp Med 191:423–433, 2000

    Google Scholar 

  34. Inaba K, Turley S, Yamaide F, Iyoda K, Mahnke K, Inaba M, Pack M, Subklewe M, Sauter B, Sheff D, Albert ML, Bharwaj N, Mellman I, Steinman RM: Efficient presentation of phagocytosed cellular fragments on the major histocompatibility complex class II products of dendritic cells. J Exp Med 188:2163–2173, 1998

    Google Scholar 

  35. Cella M, Sallusto F, Lanzavecchia A: Origin, maturation and antigen presenting function of dendrieic cells. Curr Opin Immunol 9:10–16, 1997

    Google Scholar 

  36. Thurner B, Roder C, Dieckmann D, Heuer M, Kruse M, Glaser A, Keikavoussi P, Kaempgen E, Bender A, Schuler G: Generation of large numbers of fully mature and stable dendritic cells from leukapheresis products for clinical application. J Immunol Meth 223:1–15, 1999

    Google Scholar 

  37. Tedder TF, Engel P: CD20: A regulator of cell-cycle progression of B-lymphocytes. Immunol Today 15:450–454, 1994

    Google Scholar 

  38. Press OW, Appelbaum F, Ledbetter JA, Martin PJ, Zarling J, Kidd P, Thomas ED: Monoclonal antibody 1F5 (anti CD20) serotherapy of human B-cell lymphomas. Blood 69:584–591, 1987

    Google Scholar 

  39. Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Rabb R, Newman RA, Hanna N, Anderson DR: Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83:435–445, 1994

    Google Scholar 

  40. Maloney DG, Liles TM, Czerwinski DK, Waldichuk C, Rosenber J, Grillo-Lopez A, Levy R: Phase-I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 84:2457–2466, 1994

    Google Scholar 

  41. Selenko N, Majdic O, Draxler S, Berer A, Jaeger U, Knapp W, Stoeckl J: CD20 antibody (C2B8)-induced apoptosis of lymphoma cells promotes phagocytosis by dendritic cells and cross-priming of CD8+cytotoxic T-cells. Leukemia 15:1619–1626, 2001

    Google Scholar 

  42. Seong RH, Clayberger CA, Krensky AM, Parnes JR: Rescue of Daudi cell HLA expression by transfection of the mouse β2-microglobulin gene. J Exp Med 167:288–299, 1988

    Google Scholar 

  43. Browning MJ, Madrigal JA, Krausa P, Kowalski H, Allsopp CEM, Little AM, Turner S, Adams EJ, Arnett KL, Bodmer WF, Bodmer JG, Parham P: Novel HLA-A,B,C genotype of the class-I negative cell line Daudi reveals novel HLA-A and-B alleles. Tissue Antigens 45:177–187, 1995

    Google Scholar 

  44. Calgaris-Cappio F: Relationship between autoimmunity and immunodeficiency in CLL. Hematol Cell Ther 39:13–16, 1997

    Google Scholar 

  45. Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Beratton DL, Henson PM: Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages.J Immunol 148:2207–2216, 1992

    Google Scholar 

  46. Fadok VA, Bratton DL, Rose DM, Ezekewitz RAB, Henson PM: A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405:85–90, 2000

    Google Scholar 

  47. Albert ML, Pearce SFA, Francisco LM, Sauter B, Roy P, Silverstein RY, Bhardwaj N: Immature dendritic cells phagocytose apoptotic cells via αvβ5 and CD36, and cross-present antigens to cytotoxic T-lymphocytes. J Exp Med 188:1359–1368, 1998

    Google Scholar 

  48. Krahling S, Callhan MK, Williamson P, Schlegel RA: Exposure of phosphatidylserine is a general feature in the phagocytosis of apoptotic lymphocytes by macrophages. Cell Death Diff 6:183–189, 1999

    Google Scholar 

  49. Rubartelli A, Poggi A, Zocchi MR: The selective engulfment of apoptotic bodies by dendritic cells is mediated by the αvβ3 integrin and requires intracellular and extracellular calcium. Eur J Immunol 27:1893–1900, 1997

    Google Scholar 

  50. Verhoven B, Krahling S, Schlegel RA, Williamson P: Regulation of phosphatidylserine exposure and phagocytosis of apoptotic T-lymphocytes. Cell Death Diff 6:262–270, 1999

    Google Scholar 

  51. Nelson EL, Li X, Hsu FJ, Kwak LW, Levy R, Clayberger C, Krensky AM: Tumor-specific, cytotoxic T-lymphocyte responses after idiotype vaccination for B-cell, non-Hodgkin' lymphoma. Blood 15:580–589, 1996

    Google Scholar 

  52. Davis TA, Maloney DG, Czerwinski DK, Liles TM, Levy R: Anti-idiotype antibodies can induce long-term complete remissions in non-Hodgkin' lymphoma without eradicating the malignant clone. Blood 92:1184–1190, 1998

    Google Scholar 

  53. Farrar JD, Katz KH, Windsor J, Thrush G, Scheuermann RH, Uhr JW, Street NE: Cancer dormancy. A regulatory role for CD8+T-cells and IFN-γ in establishing and maintaining the tumor dormant state. J Immunol 162:2842–2849, 1999

    Google Scholar 

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Authors and Affiliations

  1. Institute of Immunology, University of Vienna, Medical School, Vienna, Austria

    Nicole Selenko, Otto Majdic, Johannes Stöckl & Walter Knapp

  2. Department of Internal Medicine-I, Division of Haematology and Haemostaseology, University of Vienna, Medical School, Vienna, Austria

    Ulrich Jäger & Christian Sillaber

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  1. Nicole Selenko
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  2. Otto Majdic
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  3. Ulrich Jäger
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  5. Johannes Stöckl
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  6. Walter Knapp
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Correspondence to Walter Knapp.

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Selenko, N., Majdic, O., Jäger, U. et al. Cross-Priming of Cytotoxic T Cells Promoted by Apoptosis-Inducing Tumor Cell Reactive Antibodies?. J Clin Immunol 22, 124–130 (2002). https://doi.org/10.1023/A:1015463811683

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