酪氨酸激酶抑制剂对CML患者Th1、Treg细胞的影响
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摘要
目的:比较第二代酪氨酸激酶抑制剂(TKI)达沙替尼和尼洛替尼与第一代TKI伊马替尼对慢性髓系白血病(CML)患者的免疫调节作用。方法:对本中心使用达沙替尼(n=10)、尼洛替尼(n=26)或伊马替尼(n=44)治疗≥3个月的CML患者进行T细胞亚群等免疫指标的检测,并将上述指标与患者的临床疾病缓解状态及预后评估相关联分析。结果:达沙替尼、尼洛替尼和伊马替尼治疗的3组CML患者外周血Th1比例(Th1/CD4+T)高于正常值上限的例数分别为80.0%、16.6%和27.5%,其中达沙替尼组Th1比例值30.86%±9.75%显著高于尼罗替尼组17.37%±9.35%(P <0.001)和伊马替尼组20.79%±9.01%(P <0.001)。3组患者外周血CD8+T比例(CD8+T/Lymphocyte)各组无显著差异(P> 0.05), Th2比例(Th2/CD4+T)也无显著差异(P> 0.05)。Treg比例(Treg/CD4+T)达沙替尼组1.31%±0.10%显著低于尼洛替尼组2.65%±0.97%(P <0.001)和伊马替尼组2.99%±1.40%(P <0.001)。统计分析所有用药治疗后的患者:Th1比例高于正常上限25.8%的患者(n=28)中:84.62%为CCyR(完全细胞遗传学缓解),71.43%为MMR(主要分子生物学缓解),71.43%为MR4.5; Th1比例正常范围内11.8%-25.8%的患者(n=45)中:90.7%为CCyR,75.56%为MMR,75.56%为MR4.5;而Th1比例低于正常下限11.8%的患者(n=21)中:57.14%为CCyR,47.62%为MMR,47.62%为MR4.5。结果显示Th1升高组及正常组具有更高的缓解率及更深的缓解度。结论:本研究结果提示CML在TKI治疗中,Th1比例升高或正常提示更大的CCyR、MMR、MR4.5机率,而达沙替尼相比尼洛替尼及伊马替尼能显著提升患者Th1水平、降低Treg水平。
Objective: To compare the immunomodulatory effects of the 2nd generation of tyrosine kinase inhibitors(TKIs)-dasatinib and nilotinib as well as the 1st generation of TKI-imatinib on chronic myeloid leukemia(CML) patients. Method: To evaluate the T cell subtypes by flow cytometry on the CML patients of our center who received the treatment with dasatinib(n=10), nilotinib(n=26) or imatinib(n=44) for more than 3 months, and to analyze and correlate these data with the clinical remission situations and prognosis. Results: 80.0% of the patients in dasatinib group, 16.6% of the patients in nilotinib group and 27.5% of the patients in imatinib group respectively had a Th1 proportion in the peripheral blood(Th1/CD4+ T) above the upper limit of normal. More specifically, the Th1 proportion in dasatinib group(30.86%±9.75%) was significantly higher than that in nilotinib group(17.37%±9.35%)(P <0.001) and that in imatinib group(20.79%±9.01%)(P <0.001). Among the 3 groups, both the CD8+ T cell proportion(CD8+ T/Lymphocyte) and the Th2 proportion(Th2/CD4+ T) in the peripheral blood did not show a statistically significant difference. The Treg proportion(Treg/CD4+ T) in dasatinib group(1.31%±0.10%) was significantly lower than that in nilotinib group(2.65%±0.97%)(P <0.001) and that in imatinib group(2.99%±1.40%)(P <0.001).Among all the CML patients analyzed, for CML patients who had a Th1 proportion above the upper limit of normal(25.8%)(n=28), 84.62% of these patients obtained CCyR(complete cytogenetic response), 71.43% of these patients obtained MMR(major molecular response), 71.43% of these patients obtained MR4.5; for CML patients who had the Th1 proportion in the normal range(11.8%-25.8%)(n=45), 90.7% of these patients obtained CCyR, 75.56% of these patients obtained MMR, and 75.56% of these patients obtained MR4.5; for CML patients who had the Th1 proportion below the lower limit of normal(11.8%)(n=21), 57.14% of these patients obtained CCyR, 47.62% of these patients obtained MMR, and 47.62% of these patients obtained MR4.5. The above-mentioned data shows that the patients in high Th1 group and the normal Th1 group obtained the higher remission rate as well as the deeper remission level. Conclusion: This study shows that during the CML treatment with TKIs, the increased or normal Th1 proportion indicates a bigger chance for CCyR, MMR, and MR4.5. Dasatinib may significantly increase the level of Th1 while decrease the level of Treg in the patients, as compared with nilotinib and imatinib.
Objective: To compare the immunomodulatory effects of the 2nd generation of tyrosine kinase inhibitors(TKIs)-dasatinib and nilotinib as well as the 1st generation of TKI-imatinib on chronic myeloid leukemia(CML) patients. Method: To evaluate the T cell subtypes by flow cytometry on the CML patients of our center who received the treatment with dasatinib(n=10), nilotinib(n=26) or imatinib(n=44) for more than 3 months, and to analyze and correlate these data with the clinical remission situations and prognosis. Results: 80.0% of the patients in dasatinib group, 16.6% of the patients in nilotinib group and 27.5% of the patients in imatinib group respectively had a Th1 proportion in the peripheral blood(Th1/CD4+ T) above the upper limit of normal. More specifically, the Th1 proportion in dasatinib group(30.86%±9.75%) was significantly higher than that in nilotinib group(17.37%±9.35%)(P <0.001) and that in imatinib group(20.79%±9.01%)(P <0.001). Among the 3 groups, both the CD8+ T cell proportion(CD8+ T/Lymphocyte) and the Th2 proportion(Th2/CD4+ T) in the peripheral blood did not show a statistically significant difference. The Treg proportion(Treg/CD4+ T) in dasatinib group(1.31%±0.10%) was significantly lower than that in nilotinib group(2.65%±0.97%)(P <0.001) and that in imatinib group(2.99%±1.40%)(P <0.001).Among all the CML patients analyzed, for CML patients who had a Th1 proportion above the upper limit of normal(25.8%)(n=28), 84.62% of these patients obtained CCyR(complete cytogenetic response), 71.43% of these patients obtained MMR(major molecular response), 71.43% of these patients obtained MR4.5; for CML patients who had the Th1 proportion in the normal range(11.8%-25.8%)(n=45), 90.7% of these patients obtained CCyR, 75.56% of these patients obtained MMR, and 75.56% of these patients obtained MR4.5; for CML patients who had the Th1 proportion below the lower limit of normal(11.8%)(n=21), 57.14% of these patients obtained CCyR, 47.62% of these patients obtained MMR, and 47.62% of these patients obtained MR4.5. The above-mentioned data shows that the patients in high Th1 group and the normal Th1 group obtained the higher remission rate as well as the deeper remission level. Conclusion: This study shows that during the CML treatment with TKIs, the increased or normal Th1 proportion indicates a bigger chance for CCyR, MMR, and MR4.5. Dasatinib may significantly increase the level of Th1 while decrease the level of Treg in the patients, as compared with nilotinib and imatinib.
引文
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6 Larson RA.Is there a best TKI for chronic phase CML?Blood,2015;126(21):2370-2375.
7 Parsons SJ,Parsons JT.Src family kinases,key regulators of signal transduction.Oncogene,2004;23(48):7906-7909.
8 Seddon B,Zamoyska R.TCR signals mediated by Src family kinases are essential for the survival of naive T cells.J Immunol,2002;169(6):2997-3005.
9 Gu JJ,Ryu JR,Pendergast AM.Abl tyrosine kinases in T-cell signaling.Immunol Rev,2009;228(1):170-183.
10 Uchiyama T,Sato N,Narita M,et al.Direct effect of dasatinib on proliferation and cytotoxicity of natural killer cells in in vitro study.Hematol Oncol,2013;31(3):156-163.
11 Mustjoki S,Ekblom M,Arstila TP,et al.Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy.Leukemia,2009;23(8):1398-1405.
12 Finn OJ.Cancer immunology.N Engl J Med,2008;358(25):2704-2715.
13 Ribas A.Adaptive immune resistance:how cancer protects from immune attack.Cancer Discov,2015;5(9):915-919.
14 Helmy KY,Patel SA,Nahas GR,et al.Cancer immunotherapy:accomplishments to date and future promise.Ther Deliv,2013;4(10):1307-1320.
15 Frazier JL,Han JE,Lim M,et al.Immunotherapy combined with chemotherapy in the treatment of tumors.Neurosurg Clin N Am,2010;21(1):187-194.
2 Goldman JM,Melo JV.Chronic myeloid leukemia--advances in biology and new approaches to treatment.N Engl J Med,2003;349(15):1451-1464.
3 Branford S,Rudzki Z,Walsh S,et al.High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib(STI571)resistance.Blood,2002;99(9):3472-3475.
4 Zhang JF,Liu XL,Lin YD,et al.Bioinformatic analysis of chronic myeloid leukemia progression and preliminary experimental verification.Zhongguo shi yan xue ye xue za zhi,2014;22(4):909-913.
5 Wang YY,Zhao HG,Cui ZG,et al.Clinical efficacy of dasatinib,nilotinib and imatinib in newly diagnosed patients with chronicphase chronic myeloid leukemia:a three-year retrospective analysis.Zhongguo shi yan xue ye xue za zhi,2015;23(2):356-363.
6 Larson RA.Is there a best TKI for chronic phase CML?Blood,2015;126(21):2370-2375.
7 Parsons SJ,Parsons JT.Src family kinases,key regulators of signal transduction.Oncogene,2004;23(48):7906-7909.
8 Seddon B,Zamoyska R.TCR signals mediated by Src family kinases are essential for the survival of naive T cells.J Immunol,2002;169(6):2997-3005.
9 Gu JJ,Ryu JR,Pendergast AM.Abl tyrosine kinases in T-cell signaling.Immunol Rev,2009;228(1):170-183.
10 Uchiyama T,Sato N,Narita M,et al.Direct effect of dasatinib on proliferation and cytotoxicity of natural killer cells in in vitro study.Hematol Oncol,2013;31(3):156-163.
11 Mustjoki S,Ekblom M,Arstila TP,et al.Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy.Leukemia,2009;23(8):1398-1405.
12 Finn OJ.Cancer immunology.N Engl J Med,2008;358(25):2704-2715.
13 Ribas A.Adaptive immune resistance:how cancer protects from immune attack.Cancer Discov,2015;5(9):915-919.
14 Helmy KY,Patel SA,Nahas GR,et al.Cancer immunotherapy:accomplishments to date and future promise.Ther Deliv,2013;4(10):1307-1320.
15 Frazier JL,Han JE,Lim M,et al.Immunotherapy combined with chemotherapy in the treatment of tumors.Neurosurg Clin N Am,2010;21(1):187-194.