Najima Yuho, Yoshida Chikashi, Iriyama Noriyoshi, Fujisawa Shin, Wakita Hisashi, Chiba Shigeru, Okamoto Shinichiro, Kawakami Kimihiro, Takezako Naoki, Kumagai Takashi, Ohyashiki Kazuma, Taguchi Jun, Yano Shingo, Igarashi Tadahiko, Kouzai Yasuji, Morita Satoshi, Sakamoto Junichi, Sakamaki Hisashi, Inokuchi Koiti
Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
Department of Hematology, National Hospital Organization, Mito Medical Center, Higashiibarakigun, Japan.
Leuk Res. 2018 Mar;66:66-72. doi: 10.1016/j.leukres.2018.01.010. Epub 2018 Feb 3.
We evaluated the effects of regulatory T cell (Treg) inhibition during dasatinib treatment on the anticancer immune response, particularly on natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Fifty-two newly diagnosed Japanese patients with chronic myeloid leukemia (CML) in the chronic phase were enrolled in the D-first study; all received 100 mg of dasatinib once daily and were followed for at least 36 months. The cumulative deep molecular response (DMR, MR4) rate was 65% by 36 months; the 3-year overall survival was 96%. CD4 T cell counts were stable, whereas the proportion of CD4CD25CD127 (Treg) cells decreased in a time-dependent manner. The DMR rate by18 months was significantly better in low Treg patients (<5.7% at 12 months) compared to the remaining patients (odds ratio 4.07). NK cell and CTL counts at several time points were inversely correlated with Treg counts. Furthermore, the degree of NK cell differentiation (CD3CD57/CD3CD56) was closely and inversely correlated with the proportion of Treg cells throughout the observation period, and showed a gradually increasing trend. In conclusion, our results demonstrate that Treg inhibition by dasatinib contributes to better treatment response through enhancement of the immune system, particularly via NK cell differentiation.
我们评估了达沙替尼治疗期间调节性T细胞（Treg）抑制对抗癌免疫反应的影响，特别是对自然杀伤（NK）细胞和细胞毒性T淋巴细胞（CTL）的影响。52例新诊断的日本慢性期慢性髓性白血病（CML）患者纳入D-first研究；所有患者均接受每日1次100mg达沙替尼治疗，并随访至少36个月。36个月时累积深度分子反应（DMR，MR4）率为65%；3年总生存率为96%。CD4 T细胞计数稳定，而CD4CD25CD127（Treg）细胞比例呈时间依赖性下降。与其余患者相比，低Treg患者（12个月时<5.7%）18个月时的DMR率显著更高（优势比4.07）。多个时间点的NK细胞和CTL计数与Treg计数呈负相关。此外，在整个观察期内，NK细胞分化程度（CD3CD57/CD3CD56）与Treg细胞比例密切负相关，并呈逐渐上升趋势。总之，我们的结果表明，达沙替尼抑制Treg通过增强免疫系统，特别是通过NK细胞分化，有助于获得更好的治疗反应。
