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CD64 Surface Expression on Neutrophils and Monocytes Is Significantly Up-Regulated after Stimulation with Granulocyte Colony-Stimulating Factor during CHOP Chemotherapy for Patients with Non-Hodgkin’s Lymphoma

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Abstract

The present study was performed to examine whether the expression of CD64 Fc gamma receptor type I (FC7RI) on both neutrophils and monocytes can be modulated by multiple daily administrations of granulocyte colony-stimulating factor (G-CSF) to patients with non-Hodgkin's lymphoma in neutropenia caused by CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. The expression of CD64 was determined by flow cytometric analysis at the following time points: before chemotherapy, at the nadir of the neutrophil count, at the fifth day after the start of G-CSF administration, and at more than 8 days after the start of G-CSF administration. CD64 expression was enhanced in patients given G-CSF during CHOP treatment, whereas CD64 expression remained unchanged in patients not given G-CSF. CD64 expression levels on both neutrophils and monocytes were significantly up-regulated by the daily administration of G-CSF and reached peak levels at day 5 (P =.0007). Thereafter, expression on both cell types remained at almost the same levels as on day 5 for the rest of the treatment course, even though G-CSF therapy continued for 3 to 5 more days. Interestingly, CD64 expression on monocytes was already increased significantly (P =.0001) at the nadir of the neutrophil count relative to the baseline before chemotherapy and then was additionally up-regulated by day 5 after the start of G-CSF injections (P =.019). In antibody-dependent cellular cytotoxicity assays, we found that rituximab-mediated cell lysis was significantly enhanced at day 5 after the start of G-CSF treatment (P =.01). In conclusion, this study shows that multiple doses of G-CSF administered to lymphoma patients with neutropenia due to CHOP chemotherapy can enhance CD64 expression on both neutrophils and monocytes. Peak CD64 levels are reached at day 5 of G-CSF treatment, resulting in an activation of the rituximab-mediated antitumor ability of these effector cells. This finding may be useful in determining the optimal timing of administration for an antibody such as rituximab in a chemotherapeutic strategy designed to exert a maximal effect against tumor cells.

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References

  1. Reff ME, Camer K, Chambers KS, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20.Blood. 1994;83:435–445.

    PubMed  CAS  Google Scholar 

  2. Anderson KC, Bates MP, Slaughenhoupt BL, Pinkus GS, Schlossman SF, Nadler LM. Expression of human B cell-associated antigens on leukemias and lymphomas: a model of human B cell differentiation.Blood. 1984;63:1424–1433.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  4. Press OW, Appelbaum F, Ledbetter JA, et al. Monoclonal antibody 1F5 (anti-CD20) serotherapy of human B cell lymphomas.Blood. 1987;69:584–591.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  6. Golay J, Zaffaroni L, Vaccari T, et al. Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis.Blood. 2000;95:3900–3908.

    PubMed  CAS  Google Scholar 

  7. Harjunpaa A, Junnikkala S, Meri S. Rituximab (anti-CD20) therapy of B-cell lymphomas: direct complement killing is superior to cellular effector mechanisms.Scand J Immunol. 2000;51:634–641.

    Article  PubMed  CAS  Google Scholar 

  8. Idusogie EE, Presta LG, Gazzano-Santoro H, et al. Mapping of the C1q binding site on rituxan, a chimeric antibody with a human IgG1 Fc.J Immunol. 2000;164:4178–4184.

    Article  PubMed  CAS  Google Scholar 

  9. Anderson DR, Grillo-Lopez A, Varns C, Chambers KS, Hanna N. Targeted anti-cancer therapy using rituximab, a chimeric anti- CD20 antibody (IDEC-C2B8) in the treatment of non-Hodgkin’s B-cell lymphoma.Biochem Soc Trans. 1997;25:705–708.

    Article  PubMed  CAS  Google Scholar 

  10. Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets.Nat Med. 2000;6:443–446.

    Article  PubMed  CAS  Google Scholar 

  11. Voso MT, Pantel G, Rutella S, et al. Rituximab reduces the number of peripheral blood B-cells in vivo mainly by effector cell-mediated mechanisms.Haematologica. 2002;87:918–925.

    PubMed  CAS  Google Scholar 

  12. Deo YM, Graziano RF, Repp R, van de Winkel JG. Clinical significance of IgG Fc receptors and Fc-yR-directed immunotherapies.Immunol Today. 1997;18:127–135.

    Article  PubMed  CAS  Google Scholar 

  13. Hoffmeyer F, Witte K, Schmidt RE. The high-affinity Fc gamma RI on PMN: regulation of expression and signal transduction.Immunology. 1997;92:544–552.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Elsasser D, Valerius T, Repp R, et al. HLA class II as potential target antigen on malignant B cells for therapy with bispecific antibodies in combination with granulocyte colony-stimulating factor.Blood. 1996;87:3803–3812.

    PubMed  CAS  Google Scholar 

  15. Repp R, Valerius T, Sendler A, et al. Neutrophils express the high affinity receptor for IgG (FcγRI, CD64) after in vivo application of recombinant human granulocyte colony-stimulating factor.Blood. 1991;78:885–889.

    PubMed  CAS  Google Scholar 

  16. Valerius T, Repp R, de Wit TPM, et al. Involvement of the high- affinity receptor for IgG (Fc gamma RI; CD64) in enhanced tumor cell cytotoxicity of neutrophils during granulocyte colony-stimulating factor therapy.Blood. 1993;82:931–939.

    PubMed  CAS  Google Scholar 

  17. Kerst JM, de Haas M, van der Schoot CE, et al. Recombinant granulocyte colony-stimulating factor administration to healthy volunteers: induction of immunophenotypically and functionally altered neutrophils via an effect on myeloid progenitor cells.Blood. 1993;82:3265–3272.

    PubMed  CAS  Google Scholar 

  18. Stockmeyer B, Valerius T, Repp R, et al. Preclinical studies with FcγR bispecific antibodies and granulocyte colony-stimulating factor-primed neutrophils as effector cells against HER-2/neu overexpressing breast cancer.Cancer Res. 1997;57:696–701.

    PubMed  CAS  Google Scholar 

  19. Kerst JM, van de Winkel JGJ, Evans AH, et al. Granulocyte colonystimulating factor induces hFc gamma RI (CD64 antigen)-positive neutrophils via an effect on myeloid precursor cells.Blood. 1993;81:1457–1464.

    PubMed  CAS  Google Scholar 

  20. Michon J, Moutel S, Barbet J, et al. In vitro killing of neuroblastoma cells by neutrophils derived from granulocyte colony-stimulating factor-treated cancer patients using an anti-disialoganglioside/anti- FcγRI bispecific antibody.Blood. 1995;86:1124–1130.

    PubMed  CAS  Google Scholar 

  21. Maloney DG, Grillo-Lopez AJ, Bodkin DJ, et al. IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma.J Clin Oncol. 1997;15:3266–3274.

    Article  PubMed  CAS  Google Scholar 

  22. Maloney DG, Grillo-Lopez AJ, White CA, et al. IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma.Blood. 1997;90:2188–2195.

    PubMed  CAS  Google Scholar 

  23. Tobinai K, Kobayashi Y, Narabayashi M, et al. Feasibility and pharmacokinetic study of a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) in relapsed B cell lymphoma: the IDEC- C2B8 Study Group.Ann Oncol. 1998;9:527–534.

    Article  PubMed  CAS  Google Scholar 

  24. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program.J Clin Oncol. 1998;16:2825–2833.

    Article  PubMed  CAS  Google Scholar 

  25. Hainsworth JD, Burris HA III, Morissey LH, et al. Rituximab monoclonal antibody as initial systemic therapy for patients with low-grade non-Hodgkin lymphoma.Blood. 2000;95:3052–3056.

    PubMed  CAS  Google Scholar 

  26. Colombat P, Salles G, Brousse N, et al. Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation.Blood. 2001;97:101–106.

    Article  PubMed  CAS  Google Scholar 

  27. Czuczman MS, Grillo-Lopez AJ, White CA, et al. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy.J Clin Oncol. 1999;17:268–276.

    Article  PubMed  CAS  Google Scholar 

  28. Vose JM, Link BK, Grossbard ML, et al. Phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated aggressive non-Hodgkin's lymphoma.J Clin Oncol. 2001;19:389–397.

    Article  PubMed  CAS  Google Scholar 

  29. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma.N Engl J Med. 2002;346:235–242.

    Article  PubMed  CAS  Google Scholar 

  30. Michon JM, Gey A, Moutel S, et al. In vivo induction of functional FcγRI (CD64) on neutrophils and modulation of blood cytokine mRNA levels in cancer patients treated with G-CSF (rMetHuG- CSF).Br J Haematol. 1998;100:550–556.

    Article  PubMed  CAS  Google Scholar 

  31. Schmidt RE, Perussia B. Cluster report: CD16. In: Knapp W, Dörken B, Gilks WR, et al, eds. Leucocyte Typing IV, White Cell Differentiation Antigens. Oxford, UK: Oxford University Press. 1989:574–578.

    Google Scholar 

  32. Stroncek DF, Jaszcz W, Herr GP, Clay ME, McCullough J. Expression of neutrophil antigens after 10 days of granulocyte-colonystimulating factor.Transfusion. 1998;38:663–668.

    Article  PubMed  CAS  Google Scholar 

  33. Ohsaka A, Saionji K, Kuwaki T, Takeshima T, Igari J. Granulocyte colony-stimulating factor administration modulates the surface expression of effector cell molecules on human monocytes.Br J Haematol. 1995;89:465–472.

    Article  PubMed  CAS  Google Scholar 

  34. Demetri GD, Griffin JD. Granulocyte colony-stimulating factor and its receptor.Blood. 1991;78:2791–2808.

    PubMed  CAS  Google Scholar 

  35. Nicola NA. Hemopoietic cell growth factors and their receptors.Ann Rev Biochem. 1989;58:45–77.

    Article  PubMed  CAS  Google Scholar 

  36. Lord BI, Molineux G, Pojda Z, Souza LM, Mermod J-J, Dexter TM. Myeloid cell kinetics in mice treated with recombinant interleukin-3, granulocyte colony-stimulating factor (CSF), or granulocyte-macrophage CSF in vivo.Blood. 1991;77:2154–2159.

    PubMed  CAS  Google Scholar 

  37. Gericke GH, Ericson SG, Pan L, Mills LE, Guyre PM, Ely P. Mature polymorphonuclear leukocytes express high-affinity receptors for IgG (FcγRI) after stimulation with granulocyte colony-stimulating factor (G-CSF).J Leukoc Biol. 1995;57:455–461.

    Article  PubMed  CAS  Google Scholar 

  38. Bovolenta C, Gasperini S, Cassatella MA. Granulocyte colony- stimulating factor induces the binding of STAT 1 and STAT 3 to the IFNγ response region within the promoter of the FcγRI/CD64 gene in human neutrophils.FEBS Lett. 1996;386:239–242.

    Article  PubMed  CAS  Google Scholar 

  39. Stockmeyer B, Schiller M, Repp R, et al. Enhanced killing of B lymphoma cells by granulocyte colony-stimulating factor-primed effector cells and Hu1D10—a humanized human leucocyte antigen DR antibody.Br J Haematol. 2002;118:959–967.

    Article  PubMed  CAS  Google Scholar 

  40. van der Kolk LE, de Haas M, Grillo-Lopez AJ, Baars JW, van Oers MHJ. Analysis of CD20-dependent cellular cytotoxicity by G-CSF-stimulated neutrophils.Leukemia. 2002;16:639–699.

    Google Scholar 

  41. Cartron G, Dacheux L, Salles G, et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcγRIIIa gene.Blood. 2002;99:754–758.

    Article  PubMed  CAS  Google Scholar 

  42. Weber JS, Yang JC, Topalian SL, Schwartzentruber DJ, White DE, Rosenberg SA. The use of interleukin 2 and lymphokine-activated killer cells for the treatment of patients with non-Hodgkin’s lymphoma.J Clin Oncol. 1992;10:33–40.

    Article  PubMed  CAS  Google Scholar 

  43. Friedberg JW, Neuberg D, Gribben JG, et al. Combination immunotherapy with rituximab and interleukin 2 in patients with relapsed or refractory follicular non-Hodgkin's lymphoma.Br J Haematol. 2002;117:828–834.

    Article  PubMed  CAS  Google Scholar 

  44. Davis TA, Maloney DG, Grillo-Lopez CA, et al. Combination immunotherapy of relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma with rituximab and interferon-α-2a.Clin Cancer Res. 2000;6:2644–2652.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine, Asahikawa Kosei Hospital, 1-24, Asahikawa, 078-8211, Japan

    Yasutaka Kakinoki, Hiroya Kubota & Yasushi Yamamoto

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  1. Yasutaka Kakinoki
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  2. Hiroya Kubota
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  3. Yasushi Yamamoto
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Correspondence to Yasushi Yamamoto.

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Kakinoki, Y., Kubota, H. & Yamamoto, Y. CD64 Surface Expression on Neutrophils and Monocytes Is Significantly Up-Regulated after Stimulation with Granulocyte Colony-Stimulating Factor during CHOP Chemotherapy for Patients with Non-Hodgkin’s Lymphoma. Int J Hematol 79, 55–62 (2004). https://doi.org/10.1007/BF02983535

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