Dahuang Fuzi Baijiang decoction restricts progenitor to terminally exhausted T cell differentiation in colorectal cancer.
Dahuang Fuzi Baijiang decoction restricts progenitor to terminally exhausted T cell differentiation in colorectal cancer.
复制标题
作者：
肥胖会使结直肠癌（CRC）的风险增加30%。肥胖肿瘤微环境通过引发耗竭的T细胞（Tex）而损害抗肿瘤免疫。从《金匮要略》中推测大黄附子白姜汤为合经方。我们首先确定DFB通过扩大具有程序性细胞死亡-1（PD-1 intTIM 3-）的中间表达的TIM 3-亚群并限制PD-1hiTIM 3+亚群来使高脂饮食诱导的肥胖小鼠的肿瘤生长消退。转录因子1（TCF 1）在PD-1 intTIM 3-亚群中高度表达，但在PD-1hiTIM 3+细胞中不存在。我们接下来证实了祖细胞PD-1 intTCF+细胞强烈产生肿瘤坏死因子-α（TNFα）和干扰素-γ，而终末分化的PD-1 intTCF+细胞在产生TNFα方面存在缺陷。对于转基因ob/ob小鼠，我们发现DFB通过限制PD-1hiTim 3+亚群和扩增PD-1 intTCF+群体与抗PD-1（αPD-1）产生协同效应。最后，我们将重组趋化因子C-C-基序受体2（CCR 2）+CD 8+亚群定义为末端Tex，并确定从祖细胞到末端Tex的分化至少部分由趋化因子（C-C基序）配体2（CCL 2）/CCR 2轴驱动。CCR 2抑制剂通过促进祖细胞Tex的计数来增强对αPD-1的应答。总之，DFB抑制CCL 2并在肥胖微环境中保留祖细胞Tex以抑制CRC进展。这些发现提供了明确的证据，表明传统中药配方DFB可以通过调节适应性免疫来预防肿瘤进展，并为进一步的临床验证建立了强有力的理论基础。大黄附子白姜汤（DFB）通过限制PD-1hiTim 3+亚群和扩增PD-1 intTCF+群体，与抗程序性细胞死亡-1（PD-1）产生协同效应。DFB抑制CCL 2并在肥胖微环境中保留祖细胞终末耗尽的T细胞以抑制结直肠癌进展。
Obesity increases the risk of colorectal cancer (CRC) by 30%. The obese tumor microenvironment compromises antitumor immunity by eliciting exhausted T cells (Tex). Hypothesizing that Dahuang Fuzi Baijiang decoction (DFB) is a combined classical prescription from the “Synopsis of Prescriptions of the Golden Chamber”. We first determined that DFB regresses tumor growth in high‐fat diet–induced obese mice by expanding the TIM3− subset with intermediate expression of programmed cell death‐1 (PD‐1intTIM3−) and restricting the PD‐1hiTIM3+ subset. Transcription factor 1 (TCF1) is highly expressed in the PD‐1intTIM3− subset but is absent in PD‐1hiTIM3+ cells. We next confirmed that progenitor PD‐1intTCF+ cells robustly produce tumor necrosis factor‐α (TNFα) and interferon‐γ, whereas terminally differentiated PD‐1intTCF+ cells have defects in generating TNFα. With transgenic ob/ob mice, we found that DFB produces cooperative efficacy with anti‐PD‐1 (αPD‐1) by limiting the PD‐1hiTim3+ subset and amplifying the PD‐1intTCF+ population. Finally, we defined the recombinant chemokine C‐C‐motif receptor 2 (CCR2)+CD8+ subset as terminal Tex and identified that the differentiation from progenitor to terminal Tex is driven, at least in part, by the chemokine (C‐C motif) ligand 2 (CCL2)/CCR2 axis. The CCR2 inhibitor enhances the response to αPD‐1 by promoting the counts of progenitor Tex. Altogether, DFB dampens CCL2 and preserves progenitor Tex in the obese microenvironment to restrain CRC progression. These findings provide unambiguous evidence that the traditional Chinese formula DFB can prevent tumor progression by modulating adaptive immunity and establish a strong rationale for further clinical verification. Dahuang Fuzi Baijiang decoction (DFB) produces cooperative efficacy with anti‐programmed cell death‐1 (PD‐1) by limiting the PD‐1hiTim3+ subset and amplifying the PD‐1intTCF+ population. DFB dampens CCL2 and preserves progenitor terminal exhausted T cells in the obese microenvironment to restrain colorectal cancer progression.
登录
查看更多内容
DOI：
10.15585/mmwr.mm6639e1
发表时间：
2017-10-03
期刊：
MMWR. Morbidity and mortality weekly report
影响因子：
--
作者：
Steele CB;Thomas CC;Henley SJ;Massetti GM;Galuska DA;Agurs-Collins T;Puckett M;Richardson LC
通讯作者：
Richardson LC
影响因子：
5.9
作者：
Tu MM;Abdel-Hafiz HA;Jones RT;Jean A;Hoff KJ;Duex JE;Chauca-Diaz A;Costello JC;Dancik GM;Tamburini BAJ;Czerniak B;Kaye J;Theodorescu D
通讯作者：
Theodorescu D
影响因子：
30.5
作者：
Kanneganti, Thirumala-Devi;Dixit, Vishwa Deep
通讯作者：
Dixit, Vishwa Deep
影响因子：
11.5
作者：
Sinicrope, Frank A.;Foster, Nathan R.;Rankin, Cathryn
通讯作者：
Rankin, Cathryn
DOI：
10.1084/jem.20100643
发表时间：
2010-09-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Sakuishi K;Apetoh L;Sullivan JM;Blazar BR;Kuchroo VK;Anderson AC
通讯作者：
Anderson AC