Adapting a transforming growth factor β-related tumor protection strategy to enhance antitumor immunity
Adapting a transforming growth factor β-related tumor protection strategy to enhance antitumor immunity
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DOI：
10.1182/blood.v99.9.3179
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发表时间：
2002-05-01
期刊：
影响因子：
20.3
通讯作者：
Rooney, CM
中科院分区：
文献类型：
--
作者：
Bollard, CM;Rössig, C;Rooney, CM
转化生长因子β（TGF -β）是一种调节细胞生长和分化的多效性细胞因子，由许多人类肿瘤分泌，并显著抑制肿瘤特异性细胞免疫。肿瘤可通过表达无功能的TGF -β受体来避免TGF -β的分化和凋亡作用。我们已经确定是否可以利用这种免疫逃避策略来保护肿瘤特异性细胞毒性T淋巴细胞（CTL）免受肿瘤来源的TGF -β的抑制作用。我们以爱泼斯坦 - 巴尔病毒（EBV）特异性CTL作为模型，这些CTL被注入用于治疗EBV阳性的霍奇金病，但易受该肿瘤产生的TGF -β的影响。CTL用表达显性负性TGF -βⅡ型受体HATGF -βRII - Δcyt的逆转录病毒载体进行转导。HATGF -βRII - Δcyt转导的CTL（而非绿色荧光蛋白（eGFP）转导的CTL）对外源性TGF -β的抗增殖和抗细胞毒性作用具有抗性。此外，受体转导的细胞在抗原刺激下继续分泌细胞因子。TGF -β受体的连接导致Smad2磷酸化，而在HATGF -βRII - Δcyt转导的CTL中该通路被阻断，证实了信号转导通路被阻断。TGF -βRII - Δcyt的长期表达不影响CTL的功能、表型或生长特性。在分泌TGF -β的肿瘤存在的情况下，表达HATGF -βRII - Δcyt的肿瘤特异性CTL相对于未修饰的CTL应具有选择性的功能和生存优势，并且可能在这些疾病的治疗中具有价值。（C）2002年美国血液学会版权所有。
Transforming growth factor beta (TGF-beta), a pleiotropic cytokine that regulates cell growth and differentiation, is secreted by many human tumors and markedly inhibits tumor-specific cellular immunity. Tumors can avoid the differentiating and apoptotic effects of TGF-beta by expressing a nonfunctional TGF-beta receptor. We have determined whether this immune evasion strategy can be manipulated to shield tumor-specific cytotoxic T lymphocytes (CTLs) from the inhibitory effects of tumor-derived TGF-beta. As our model we used Epstein-Barr virus (EBV)-specific CTLs that are infused as treatment for EBV-positive Hodgkin disease but that are vulnerable to the TGF-beta produced by this tumor. CTLs were transduced with a retrovirus vector expressing the dominant-negative TGF-beta type 11 receptor HATGF-betaRII-Deltacyt. HATGF-betaRII-Deltacyt- but not green fluorescence protein (eGFP)-transduced CTLs was resistant to the anti proliferative and anticytotoxic effects of exogenous TGF-beta. Additionally, receptor-transduced cells continued to secrete cytokines in response to antigenic stimulation. TGF-beta receptor ligation results in phosphorylation of Smad2, and this pathway was disrupted in HATGF-betaRII-Deltacyt- transduced CTLs, confirming blockade of the signal transduction pathway. Long-term expression of TGF-betaRII-Deltacyt did not affect CTL function, phenotype, or growth characteristics. Tumor-specific CTLs expressing HATGF-betaRII-Deltacyt should have a selective functional and survival advantage over unmodified CTLs in the presence of TGF-beta-secreting tumors and may be of value in treatment of these diseases. (C) 2002 by The American Society of Hematology.