Stroma secreted IL6 selects for "stem-like" population and alters pancreatic tumor microenvironment by reprogramming metabolic pathways.
Stroma secreted IL6 selects for "stem-like" population and alters pancreatic tumor microenvironment by reprogramming metabolic pathways.
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DOI：
10.1038/s41419-020-03168-4
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发表时间：
2020-11-11
影响因子：
9
通讯作者：
Banerjee S
中科院分区：
文献类型：
--
作者：
Kesh K;Garrido VT;Dosch A;Durden B;Gupta VK;Sharma NS;Lyle M;Nagathihalli N;Merchant N;Saluja A;Banerjee S
胰腺癌是一种毁灭性疾病，生存率极低，仅为 9%。胰腺癌的特征是强大的纤维炎症和促纤维增生基质，为开发这种疾病的可行治疗策略带来了挑战。除了收缩血管和阻止药物有效输送到肿瘤之外，基质还有助于癌症的侵袭性生物学及其免疫逃避的微环境。在这项研究中，我们表明，在胰腺肿瘤中，发育中的基质通过富集 CD133 + 攻击性“干细胞样”细胞来增加体内胰腺癌细胞的肿瘤起始频率。此外，基质成纤维细胞分泌IL6作为主要细胞因子，增加胰腺肿瘤细胞中的糖酵解通量，并通过激活STAT信号通路增加微环境中的乳酸流出。我们还表明，分泌的乳酸有利于肿瘤微环境中 M2 巨噬细胞的激活，从而排除了肿瘤中的 CD8 + T 细胞。我们的数据还证实，用抗 IL6 抗体治疗胰腺肿瘤会导致肿瘤消退以及肿瘤内 CD133 + 群体的减少。此外，抑制微环境中的乳酸外流会减少 M2 巨噬细胞，并使胰腺肿瘤对抗 PD1 治疗更敏感。这表明基质 IL6 驱动的代谢重编程在免疫逃避微环境的发展中发挥着重要作用。总之，我们的研究表明，针对受基质 IL6 影响的代谢途径可以使胰腺肿瘤适合检查点抑制剂治疗。
Pancreatic adenocarcinoma is a devastating disease with an abysmal survival rate of 9%. A robust fibro-inflammatory and desmoplastic stroma, characteristic of pancreatic cancer, contribute to the challenges in developing viable therapeutic strategies in this disease. Apart from constricting blood vessels and preventing efficient drug delivery to the tumor, the stroma also contributes to the aggressive biology of cancer along with its immune-evasive microenvironment. In this study, we show that in pancreatic tumors, the developing stroma increases tumor initiation frequency in pancreatic cancer cells in vivo by enriching for CD133 + aggressive “stem-like” cells. Additionally, the stromal fibroblasts secrete IL6 as the major cytokine, increases glycolytic flux in the pancreatic tumor cells, and increases lactate efflux in the microenvironment via activation of the STAT signaling pathway. We also show that the secreted lactate favors activation of M2 macrophages in the tumor microenvironment, which excludes CD8 + T cells in the tumor. Our data additionally confirms that the treatment of pancreatic tumors with anti-IL6 antibody results in tumor regression as well as decreased CD133 + population within the tumor. Furthermore, inhibiting the lactate efflux in the microenvironment reduces M2 macrophages, and makes pancreatic tumors more responsive to anti-PD1 therapy. This suggests that stromal IL6 driven metabolic reprogramming plays a significant role in the development of an immune-evasive microenvironment. In conclusion, our study shows that targeting the metabolic pathways affected by stromal IL6 can make pancreatic tumors amenable to checkpoint inhibitor therapy.
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影响因子：
--
作者：
Nagathihalli NS;Castellanos JA;VanSaun MN;Dai X;Ambrose M;Guo Q;Xiong Y;Merchant NB
通讯作者：
Merchant NB
影响因子：
1.5
作者：
Chytil, A;Magnuson, MA;Moses, HL
通讯作者：
Moses, HL
影响因子：
5.7
作者：
Long KB;Tooker G;Tooker E;Luque SL;Lee JW;Pan X;Beatty GL
通讯作者：
Beatty GL
CD133+肿瘤在胰腺癌的合成鼠模型中启动细胞对Minnelide有反应。
DOI：
10.1158/1078-0432.ccr-13-2947
发表时间：
2014-05-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Banerjee S;Nomura A;Sangwan V;Chugh R;Dudeja V;Vickers SM;Saluja A
通讯作者：
Saluja A
影响因子：
11.2
作者：
Adorno-Cruz V;Kibria G;Liu X;Doherty M;Junk DJ;Guan D;Hubert C;Venere M;Mulkearns-Hubert E;Sinyuk M;Alvarado A;Caplan AI;Rich J;Gerson SL;Lathia J;Liu H
通讯作者：
Liu H