Anti-CD20 antibody induces the improvement of cytokine-induced killer cell activity via the STAT and MAPK/ERK signaling pathways

Deng,Qi; Bai,Xue; Lv,Hai‑Rong; Xiao,Xia; Zhao,Ming‑Feng; Li,Yu‑Ming

doi:10.3892/etm.2015.2264

Anti-CD20 antibody induces the improvement of cytokine-induced killer cell activity via the STAT and MAPK/ERK signaling pathways

Authors:
- Qi Deng
- Xue Bai
- Hai‑Rong Lv
- Xia Xiao
- Ming‑Feng Zhao
- Yu‑Ming Li
View Affiliations

Affiliations: Department of Hematology, Tianjin First Central Hospital, Tianjin 300192, P.R. China
Published online on: February 5, 2015 https://doi.org/10.3892/etm.2015.2264
Pages: 1215-1222

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

There is a current requirement for novel therapeutic strategies for the treatment of hematopoietic tumors. Residual tumor cells are the main origin of tumor relapse. The aim of this study was to eliminate the residual tumor cells of hematopoietic tumors. Cytokine‑induced killer (CIK) cells are used in immunotherapy to deplete the residual cells. However, it is necessary to increase the antitumor activity and clinical applicability of CIK cells. The present study investigated the antitumor activity of CIK cells to the SU‑DHL2 human B‑cell lymphoma and K562 human chronic myelogenous leukemia cell lines. CD3+CD56+ cells from healthy donors were expanded in culture with cytokines and anti‑CD20 monoclonal antibody (mAb; rituximab) to generate CIK cells. A preliminary investigation of their mechanism was then performed. The increase in the cytotoxicity of the CIK cells induced by the anti‑CD20 mAb was associated with an increase in the expression of cytotoxic factors. The expression of components of the signal transducer and activator of transcription (STAT) and mitogen‑activated protein kinase/extracellular signal‑regulated kinase (MAPK/ERK) signaling pathways was found to increase. Upregulation of the expression of STAT1, STAT3 and STAT5 is important as these co‑stimulatory molecules enhance T‑cell proliferation. Activation of the MAPK signaling pathway is a possible mechanism for the anti‑apoptosis effect on the proliferation of CIK cells. In conclusion, anti‑CD20 mAb may play an important role in the improvement of CIK‑mediated cytotoxicity to tumor cells. These observations may aid in the improvement of the effects of immunotherapy in depleting the residual cells of hematopoietic tumors. Thus, the use of CIK cells cultured with anti‑CD20 mAb could be a novel therapeutic strategy for the depletion of chemotherapy‑resistant or residual cells in anaplastic large and B‑cell lymphoma.

View Figures

View References

1	Dölken G: Detection of minimal residual disease. Adv Cancer Res. 82:133–185. 2001. View Article : Google Scholar : PubMed/NCBI
2	Scheffold C, Brandt K, Johnston V, et al: Potential of autologous immunologic effector cells for bone marrow purging in patients with chronic myeloid leukemia. Bone Marrow Transplant. 15:33–39. 1995.PubMed/NCBI
3	Nagaraj S, Ziske C and Schmidt-Wolf IG: Human cytokine-induced killer cells have enhanced in vitro cytolytic activity via non-viral interleukin-2 gene transfer. Genet Vaccines Ther. 2:122004. View Article : Google Scholar : PubMed/NCBI
4	Edinger M, Cao YA, Verneris MR, et al: Revealing lymphoma growth and the efficacy of immune cell therapies using in vivo bioluminescence imaging. Blood. 101:640–648. 2003. View Article : Google Scholar
5	Marin V, Dander E, Biagi E, et al: Characterization of in vitro migratory properties of anti-CD19 chimeric receptor-redirected CIK cells for their potential use in B-ALL immunotherapy. Exp Hematol. 34:1219–1229. 2006. View Article : Google Scholar : PubMed/NCBI
6	Shi M, Zhang B, Tang ZR, et al: Autologous cytokine-induced killer cell therapy in clinical trial phase I is safe in patients with primary hepatocellular carcinoma. World J Gastroenterol. 10:1146–1151. 2004.PubMed/NCBI
7	Introna M, Borleri G, Conti E, et al: Repeated infusions of donor-derived cytokine-induced killer cells in patients relapsing after allogeneic stem cell transplantation: a phase I study. Haematologica. 92:952–959. 2007. View Article : Google Scholar : PubMed/NCBI
8	Feugier P, Van Hoof A, Sebban C, et al: Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de I’Adulte. J Clin Oncol. 23:4117–4126. 2005. View Article : Google Scholar : PubMed/NCBI
9	Habermann TM, Weller EA, Morrison VA, et al: Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 24:3121–3127. 2006. View Article : Google Scholar : PubMed/NCBI
10	Pfreundschuh M, Trümper L, Osterborg A, et al; MabThera International Trial Group. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 7:379–391. 2006. View Article : Google Scholar : PubMed/NCBI
11	Leemhuis T, Wells S, Scheffold C, et al: A phase I trial of autologous cytokine-induced killer cells for the treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma. Biol Blood Marrow Transplant. 11:181–187. 2005. View Article : Google Scholar : PubMed/NCBI
12	Linn YC and Hui KM: Cytokine-induced killer cells: NK-like T cells with cytotolytic specificity against leukemia. Leuk Lymphoma. 44:1457–1462. 2003. View Article : Google Scholar : PubMed/NCBI
13	Verneris MR, Ito M, Baker J, et al: Engineering hematopoietic grafts: purified allogeneic hematopoietic stem cells plus expanded CD8+ NK-T cells in the treatment of lymphoma. Biol Blood Marrow Transplant. 7:532–542. 2001. View Article : Google Scholar
14	Verneris MR, Karami M, Baker J, et al: Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells. Blood. 103:3065–3072. 2004. View Article : Google Scholar : PubMed/NCBI
15	Alvarnas JC, Linn YC, Hope EG and Negrin RS: Expansion of cytotoxic CD3+ CD56+ cells from peripheral blood progenitor cells of patients undergoing autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant. 7:216–222. 2001. View Article : Google Scholar : PubMed/NCBI
16	Pievani A, Belussi C, Klein C, et al: Enhanced killing of human B-cell lymphoma targets by combined use of cytokine-induced killer cell (CIK) cultures and anti-CD20 antibodies. Blood. 117:510–518. 2011. View Article : Google Scholar
17	David M: Signal transduction by type I interferons. Biotechniques Suppl. 58–65. 2002.
18	Moro H, Otero DC, Tanabe Y and David M: T cell-intrinsic and -extrinsic contributions of the IFNAR/STAT1-axis to thymocyte survival. PLoS One. 6:e249722011. View Article : Google Scholar : PubMed/NCBI
19	Zeng R, Spolski R, Casas E, et al: The molecular basis of IL-21-mediated proliferation. Blood. 109:4135–4142. 2007. View Article : Google Scholar : PubMed/NCBI
20	Eckelhart E, Warsch W, Zebedin E, et al: A novel Ncr1-Cre mouse reveals the essential role of STAT5 for NK-cell survival and development. Blood. 117:1565–1573. 2011. View Article : Google Scholar
21	Hand TW, Cui W, Jung YW, et al: Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival. Proc Natl Acad Sci USA. 107:16601–16606. 2010. View Article : Google Scholar : PubMed/NCBI
22	Santen RJ, Song RX, McPherson R, et al: The role of mitogen-activated protein (MAP) kinase in breast cancer. J Steroid Biochem Mol Biol. 80:239–256. 2002. View Article : Google Scholar : PubMed/NCBI
23	Frigo DE, Tang Y, Beckman BS, et al: Mechanism of AP-1-mediated gene expression by select organochlorines through the p38 MAPK pathway. Carcinogenesis. 25:249–261. 2004. View Article : Google Scholar
24	Antoon JW, Nitzchke AM, Martin EC, et al: Inhibition of p38 mitogen-activated protein kinase alters microRNA expression and reverses epithelial-to-mesenchymal transition. Int J Oncol. 42:1139–1150. 2013.PubMed/NCBI