白细胞介素21抗肿瘤作用研究进展
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摘要
白细胞介素-21(IL-21)是IL-2细胞因子家族成员,主要是由活化的CD4~+T细胞产生,对淋巴细胞和髓样细胞具有广泛的生物作用。IL-21从2000年发现至今,其生物学活性和介导的细胞应答免疫机制的研究已经取得了重大进展,特别是抑制血液恶性肿瘤的机制。临床研究显示外源性IL-21可诱导表达IL-21R的B细胞非霍奇金淋巴瘤(NHL)直接凋亡,使其成为具有潜力的抗淋巴瘤治疗新策略。IL-21的抗肿瘤效应主要是通过介导NK细胞和CD4~+/CD8~+T细胞的杀伤活性实现的。概述了IL-21蛋白的特征、功能及其抗肿瘤方面的临床实验,并且阐述了IL-21与CAR-T细胞和单克隆抗体联用的效果。
Interleukin-21(IL-21), a member of the IL-2 cytokine family, is predominantly produced by activated CD4~+T cells and has a variety of biological effects on lymphocytes and myeloid cells. Since its discovery in 2000, tremendous progress has been made to elucidate IL-21′s induced cellular immune response, especially in the inhibition of hematological malignancies. Preclinical studies have shown that exogenous IL-21 induced the direct apoptosis of B-cell non-Hodgkin lymphoma(NHL) B-cell with expression of IL-21 R, making it a potential new strategy for anti-lymphoma therapy. The antitumor effect of IL-21 is mainly mediated through the cytotoxic activity of NK cells and CD4~+/CD8~+T cells. This review provides an overview of the biological structure and function of IL-21 and its anti-tumor clinical trials, and illustrates the efficacy of IL-21 in combination with CAR-T cells and monoclonal antibodies.
Interleukin-21(IL-21), a member of the IL-2 cytokine family, is predominantly produced by activated CD4~+T cells and has a variety of biological effects on lymphocytes and myeloid cells. Since its discovery in 2000, tremendous progress has been made to elucidate IL-21′s induced cellular immune response, especially in the inhibition of hematological malignancies. Preclinical studies have shown that exogenous IL-21 induced the direct apoptosis of B-cell non-Hodgkin lymphoma(NHL) B-cell with expression of IL-21 R, making it a potential new strategy for anti-lymphoma therapy. The antitumor effect of IL-21 is mainly mediated through the cytotoxic activity of NK cells and CD4~+/CD8~+T cells. This review provides an overview of the biological structure and function of IL-21 and its anti-tumor clinical trials, and illustrates the efficacy of IL-21 in combination with CAR-T cells and monoclonal antibodies.
引文
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[14]ETTINGER R, SIMS G P, FAIRHURST A M, et al. IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells[J]. Journal of Immunology, 2005, 175(12):7867-7879.
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[16]ZENG R, SPOLSKI R, FINKELSTEIN S E, et al. Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function[J]. The Journal of Experimental Medicine, 2005, 201(1):139-148.
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[18]GOZAL D, SERPERO L D, CAPDEVILA O S, et al. Systemic inflammation in non-obese children with obstructive sleep apnea [J]. Sleep Medicine, 2008, 9(3):254-259.
[19]VENKATASUBRAMANIAN S, CHEEKATLA S, PAIDIPALLY P, et al. IL-21-dependent expansion of memory-like NK cells enhances protective immune responses against Mycobacterium tuberculosis[J]. Mucosal Immunology, 2017, 10(4):1031-1042.
[20]SIMPSON N, GATENBY P A, WILSON A, et al. Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus[J]. Arthritis Rheum, 2010, 62(1):234-244.
[21]GHARIBI T, MAJIDI J, KAZEMI T, et al. Biological effects of IL-21 on different immune cells and its role in autoimmune diseases[J]. Immunobiology, 2015, 221(2):357-367.
[22]DAVIS I D, SKRUMSAGER B K, CEBON J, et al. An open-label, two-arm, phase I trial of recombinant human interleukin-21 in patients with metastatic melanoma[J]. Clincal Cancer Research, 2007, 13(12):3630-3636.
[23]DAVIS I D, BRADY B, KEFFORD R F, et al. Clinical and biological efficacy of recombinant human interleukin-21 in patients with stage IV malignant melanoma without prior treatment: a phase IIa trial[J]. Clinical Cancer Research, 2009, 15(6):2123-2129.
[24]THOMPSON J A, CURTI B D, REDMAN B G, et al. Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma[J]. Journal of Clinical Oncology, 2008, 26(12):2034-2039.
[25]SCHMIDT H, BROWN J, MOURITZEN U, et al. Safety and clinical effect of subcutaneous human interleukin-21 in patients with metastatic melanoma or renal cell carcinoma: a phase I trial[J]. Clinical Cancer Research, 2010, 16(21):5312-5319.
[26]HASHMI M H, VAN VELDHUIZEN P J. Interleukin-21: updated review of phase I and II clinical trials in metastatic renal cell carcinoma, metastatic melanoma and relapsed/refractory indolent non-Hodgkin′s lymphoma[J]. Expert Opinion on Biology Therapy, 2010, 10(5):807-817.
[27]GRüNWALD V, DESAR I M, HAANEN J, et al. A phase I study of recombinant human interleukin-21 (rIL-21) in combination with sunitinib in patients with metastatic renal cell carcinoma (RCC)[J]. Acta Oncology, 2011, 50(1):121-126.
[28]TIMMERMAN J M, BYRD J C, ANDORSKY D J, et al. A phase I dose-finding trial of recombinant interleukin-21 and rituximab in relapsed and refractory low grade B-cell lymphoproliferative disorders[J]. Clinical Cancer Research, 2012, 18(20):5752-5760.
[29]BHATIA S, CURTI B, ERNSTOFF M S, et al. Recombinant interleukin-21 plus sorafenib for metastatic renal cell carcinoma: a phase 1/2 study[J]. Journal of Immunotherapy Cancer, 2014, 2:2.
[30]XU X J, SONG D G, POUSSIN M, et al. Multiparameter comparative analysis reveals differential impacts of various cytokines on CART cell phenotype and function ex vivo and in vivo[J]. Oncotarget, 2016, 7(50):82354.
[31]SABATINO M, HU J, SOMMARIVA M, et al. Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies[J]. Blood, 2016, 128(4):519-528.
[32]KL?? S, OBERSCHMIDT O, MORGAN M, et al. Optimization of human NK cell manufacturing: Fully-automated separation, improved ex vivo expansion using IL-21 with autologous feeder cells and generation of anti-CD123-CAR-expressing effector cells[J]. Human Gene Therapy, 2017, 28(10):897-913.
[33]MCMICHAEL E L, JAIME-RAMIREZ A C, GUENTERBERG K, et al. Interleukin-21 activates natural killer cell activity against cetuximab-coated pancreatic tumor cells[J]. Journal for Immunotherapy of Cancer, 2015, 3(S2):P233.
[34]EISENSTEIN M. Medicine: eyes on the target[J]. Nature, 2015, 527(7578):S110-S112.
[35]XU M, LIU M, DU X, et al. Intratumoral delivery of IL-21 overcomes anti-Her2/Neu resistance through shifting tumor-associated macrophages from M2 to M1 phenotype[J]. Journal of Immunology, 2015, 194(10):4997-5006.
[36]岳坤, 杨海瑞. 白细胞介素21与单克隆抗体联用在肿瘤治疗中的效果研究[J]. 国际生物制品学杂志, 2016, 39(3):134-137.
[2]LEWIS K E, SELBY M J, MASTERS G, et al. Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models[J]. Oncoimmunology, 2018, 7(1):e1377873.
[3]BHATT S, SAROSIEK K A, LOSSOS I S. Interleukin 21 - its potential role in the therapy of B-cell lymphomas[J]. Leuk Lymphoma, 2017, 58(1):17-29.
[4]BHATT S, MATTHEWS J, PARVIN S, et al. Direct and immune-mediated cytotoxicity of interleukin-21 contributes to antitumor effects in mantle cell lymphoma[J]. Blood, 2015, 126(13):1555-1564.
[5]PARRISH-NOVAK J, DILLON S R, NELSON A, et al. Interleukin 21 and its receptor are involved in NK cell expansion andregulation of lymphocyte function[J]. Nature, 2000, 408(6808):57-63.
[6]LEONARD W J, WAN C K. IL-21 Signaling in immunity[J]. F1000Res, 2016, 5(224): F1000 Faculty Rev-224.
[7]CHEN B, LIU Y, CHENG L. IL-21 Enhances the degradation of cartilage through the JAK-STAT signaling pathway during osteonecrosis of femoral head cartilage[J]. Inflammation, 2017, 41(2):595-605.
[8]ASAO H, OKUYAMA C, KUMAKI S, et al. Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex[J]. Journal of Immunology, 2001, 167(1):1-5.
[9]KONFORTE D, PAIGE C J. Identification of cellular intermediates and molecular pathways induced by IL-21 in human B cells[J]. Journal of Immunology, 2007, 177(12):8381-8392.
[10]XU D H, ZHU Z, WAKEFIELD M R, et al. The role of IL-11 in immunity and cancer[J]. Cancer Letters, 2015, 358(2):156-163.
[11]BHATT S, SAROSIEK K A, LOSSOS I S. Interleukin 21 - its potential role in the therapy of B-cell lymphomas[J]. Leukemia & Lymphoma, 2017, 58(1):17-29.
[12]BARJON C, MICHAUD H A, FAGES A, et al. IL-21 promotes the development of a CD73-positive Vγ9Vδ2 T cell regulatory population[J]. Oncoimmunology, 2017, 7(1):e1379642.
[13]JIN H, CARRIO R, YU A, et al. Distinct activation signals determine whether IL-21 induces B cell costimulation, growth arrest, or Bim-dependent apoptosis[J]. Journal of Immunology, 2004, 173(1):657-665.
[14]ETTINGER R, SIMS G P, FAIRHURST A M, et al. IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells[J]. Journal of Immunology, 2005, 175(12):7867-7879.
[15]CROCE M, RIGO V, FERRINI S. IL-21: a pleiotropic cytokine with potential applications in oncology[J]. Journal of Immunology Research, 2015, 2015:1-15.
[16]ZENG R, SPOLSKI R, FINKELSTEIN S E, et al. Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function[J]. The Journal of Experimental Medicine, 2005, 201(1):139-148.
[17]LI Y, BLEAKLEY M, YEE C. IL-21 influences the frequency, phenotype, and affinity of the antigen-specific CD8+ T cell response[J]. Journal of Immunology, 2005, 175(4):2261-2269.
[18]GOZAL D, SERPERO L D, CAPDEVILA O S, et al. Systemic inflammation in non-obese children with obstructive sleep apnea [J]. Sleep Medicine, 2008, 9(3):254-259.
[19]VENKATASUBRAMANIAN S, CHEEKATLA S, PAIDIPALLY P, et al. IL-21-dependent expansion of memory-like NK cells enhances protective immune responses against Mycobacterium tuberculosis[J]. Mucosal Immunology, 2017, 10(4):1031-1042.
[20]SIMPSON N, GATENBY P A, WILSON A, et al. Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus[J]. Arthritis Rheum, 2010, 62(1):234-244.
[21]GHARIBI T, MAJIDI J, KAZEMI T, et al. Biological effects of IL-21 on different immune cells and its role in autoimmune diseases[J]. Immunobiology, 2015, 221(2):357-367.
[22]DAVIS I D, SKRUMSAGER B K, CEBON J, et al. An open-label, two-arm, phase I trial of recombinant human interleukin-21 in patients with metastatic melanoma[J]. Clincal Cancer Research, 2007, 13(12):3630-3636.
[23]DAVIS I D, BRADY B, KEFFORD R F, et al. Clinical and biological efficacy of recombinant human interleukin-21 in patients with stage IV malignant melanoma without prior treatment: a phase IIa trial[J]. Clinical Cancer Research, 2009, 15(6):2123-2129.
[24]THOMPSON J A, CURTI B D, REDMAN B G, et al. Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma[J]. Journal of Clinical Oncology, 2008, 26(12):2034-2039.
[25]SCHMIDT H, BROWN J, MOURITZEN U, et al. Safety and clinical effect of subcutaneous human interleukin-21 in patients with metastatic melanoma or renal cell carcinoma: a phase I trial[J]. Clinical Cancer Research, 2010, 16(21):5312-5319.
[26]HASHMI M H, VAN VELDHUIZEN P J. Interleukin-21: updated review of phase I and II clinical trials in metastatic renal cell carcinoma, metastatic melanoma and relapsed/refractory indolent non-Hodgkin′s lymphoma[J]. Expert Opinion on Biology Therapy, 2010, 10(5):807-817.
[27]GRüNWALD V, DESAR I M, HAANEN J, et al. A phase I study of recombinant human interleukin-21 (rIL-21) in combination with sunitinib in patients with metastatic renal cell carcinoma (RCC)[J]. Acta Oncology, 2011, 50(1):121-126.
[28]TIMMERMAN J M, BYRD J C, ANDORSKY D J, et al. A phase I dose-finding trial of recombinant interleukin-21 and rituximab in relapsed and refractory low grade B-cell lymphoproliferative disorders[J]. Clinical Cancer Research, 2012, 18(20):5752-5760.
[29]BHATIA S, CURTI B, ERNSTOFF M S, et al. Recombinant interleukin-21 plus sorafenib for metastatic renal cell carcinoma: a phase 1/2 study[J]. Journal of Immunotherapy Cancer, 2014, 2:2.
[30]XU X J, SONG D G, POUSSIN M, et al. Multiparameter comparative analysis reveals differential impacts of various cytokines on CART cell phenotype and function ex vivo and in vivo[J]. Oncotarget, 2016, 7(50):82354.
[31]SABATINO M, HU J, SOMMARIVA M, et al. Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies[J]. Blood, 2016, 128(4):519-528.
[32]KL?? S, OBERSCHMIDT O, MORGAN M, et al. Optimization of human NK cell manufacturing: Fully-automated separation, improved ex vivo expansion using IL-21 with autologous feeder cells and generation of anti-CD123-CAR-expressing effector cells[J]. Human Gene Therapy, 2017, 28(10):897-913.
[33]MCMICHAEL E L, JAIME-RAMIREZ A C, GUENTERBERG K, et al. Interleukin-21 activates natural killer cell activity against cetuximab-coated pancreatic tumor cells[J]. Journal for Immunotherapy of Cancer, 2015, 3(S2):P233.
[34]EISENSTEIN M. Medicine: eyes on the target[J]. Nature, 2015, 527(7578):S110-S112.
[35]XU M, LIU M, DU X, et al. Intratumoral delivery of IL-21 overcomes anti-Her2/Neu resistance through shifting tumor-associated macrophages from M2 to M1 phenotype[J]. Journal of Immunology, 2015, 194(10):4997-5006.
[36]岳坤, 杨海瑞. 白细胞介素21与单克隆抗体联用在肿瘤治疗中的效果研究[J]. 国际生物制品学杂志, 2016, 39(3):134-137.