Division of Surgical Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, California, United States of America.
PLoS One. 2010 Sep 15;5(9):e12711. doi: 10.1371/journal.pone.0012711.
The effects on cell signalling networks upon blockade of cytotoxic T lymphocyte-associated antigen-4 (CTLA4) using the monoclonal antibody tremelimumab were studied in peripheral blood mononuclear cell (PBMC) samples from patients with metastatic melanoma.
METHODOLOGY/PRINCIPAL: Findings Intracellular flow cytometry was used to detect phosphorylated (p) signaling molecules downstream of the T cell receptor (TCR) and cytokine receptors. PBMC from tremelimumab-treated patients were characterized by increase in pp38, pSTAT1 and pSTAT3, and decrease in pLck, pERK1/2 and pSTAT5 levels. These changes were noted in CD4 and CD8 T lymphocytes but also in CD14 monocytes. A divergent pattern of phosphorylation of Zap70, LAT, Akt and STAT6 was noted in patients with or without an objective tumor response.
CONCLUSIONS/SIGNIFICANCE: The administration of the CTLA4-blocking antibody tremelimumab to patients with metastatic melanoma influences signaling networks downstream of the TCR and cytokine receptors both in T cells and monocytes. The strong modulation of signaling networks in monocytes suggests that this cell subset may be involved in clinical responses to CTLA4 blockade.
clinicaltrials.gov; Registration numbers NCT00090896 and NCT00471887.
使用单克隆抗体 tremelimumab 阻断细胞毒性 T 淋巴细胞相关抗原 4（CTLA4）对转移性黑色素瘤患者外周血单核细胞（PBMC）样本中的细胞信号转导网络的影响进行了研究。
方法/原理：通过细胞内流式细胞术检测 TCR 和细胞因子受体下游的磷酸化（p）信号分子。用 tremelimumab 治疗的患者的 PBMC 表现为 pp38、pSTAT1 和 pSTAT3 增加，pLck、pERK1/2 和 pSTAT5 水平降低。这些变化不仅在 CD4 和 CD8 T 淋巴细胞中，而且在 CD14 单核细胞中也观察到。在有或没有客观肿瘤反应的患者中，Zap70、LAT、Akt 和 STAT6 的磷酸化呈现出不同的模式。
结论/意义：在转移性黑色素瘤患者中给予 CTLA4 阻断抗体 tremelimumab 会影响 TCR 和细胞因子受体下游的信号转导网络，无论是在 T 细胞还是单核细胞中。单核细胞中信号转导网络的强烈调节表明该细胞亚群可能参与 CTLA4 阻断的临床反应。
clinicaltrials.gov；注册号 NCT00090896 和 NCT00471887。
