Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy.
Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy.
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DOI：
10.1016/j.cmet.2018.02.024
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发表时间：
2018-05-01
期刊：
影响因子：
29
通讯作者：
Peng W
中科院分区：
文献类型：
--
作者：
Cascone T;McKenzie JA;Mbofung RM;Punt S;Wang Z;Xu C;Williams LJ;Wang Z;Bristow CA;Carugo A;Peoples MD;Li L;Karpinets T;Huang L;Malu S;Creasy C;Leahey SE;Chen J;Chen Y;Pelicano H;Bernatchez C;Gopal YNV;Heffernan TP;Hu J;Wang J;Amaria RN;Garraway LA;Huang P;Yang P;Wistuba II;Woodman SE;Roszik J;Davis RE;Davies MA;Heymach JV;Hwu P;Peng W
过继T细胞疗法(ACT)在一些癌症患者中产生持久的反应；然而，大多数肿瘤对ACT是难治性的，耐药的分子机制尚不清楚。使用两种独立的方法，我们确定肿瘤糖酵解是与黑色素瘤免疫抵抗相关的途径。糖酵解相关基因在T细胞渗透不良的黑色素瘤和肺癌患者样本中上调。糖酵解相关分子的过表达降低了T细胞对肿瘤细胞的杀伤作用，而抑制糖酵解在体内外增强了T细胞介导的抗肿瘤免疫。此外，ACT耐药患者的黑色素瘤组织中糖酵解相关基因的表达较高，来自这些患者的肿瘤细胞具有较高的糖酵解活性。我们发现在高度糖酵解黑色素瘤细胞中IRF1和CXCL10免疫刺激分子水平降低。我们的研究结果表明，肿瘤糖酵解与ACT的疗效相关，并将糖酵解途径确定为联合治疗干预的候选靶点。XXX等人发现肿瘤糖酵解与过继T细胞治疗(ACT)的免疫抵抗有关。在接受ACT治疗的患者中，肿瘤糖酵解活性的增加与较低的治疗反应有关，这突显了将糖酵解抑制与ACT结合在癌症患者中的治疗潜力。
Adoptive T cell therapy (ACT) produces durable responses in some cancer patients; however, most tumors are refractory to ACT and the molecular mechanisms underlying resistance are unclear. Using two independent approaches, we identified tumor glycolysis as a pathway associated with immune resistance in melanoma. Glycolysis-related genes were upregulated in melanoma and lung cancer patient samples poorly infiltrated by T cells. Overexpression of glycolysis-related molecules impaired T cell killing of tumor cells, whereas inhibition of glycolysis enhanced T cell-mediated antitumor immunity in vitro and in vivo. Moreover, glycolysis-related gene expression was higher in melanoma tissues from ACT-refractory patients, and tumor cells derived from these patients exhibited higher glycolytic activity. We identified reduced levels of IRF1 and CXCL10 immunostimulatory molecules in highly glycolytic melanoma cells. Our findings demonstrate that tumor glycolysis is associated with the efficacy of ACT and identify the glycolysis pathway as a candidate target for combinatorial therapeutic intervention. XXX et al identify tumor glycolysis to be associated with immune resistance to adoptive T cell therapy (ACT). In ACT-treated patients, increased tumor glycolytic activity is associated with lower therapeutic response, highlighting the therapeutic potential of combining glycolysis inhibition with ACT in cancer patients.
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影响因子：
64.5
作者：
Benci JL;Xu B;Qiu Y;Wu TJ;Dada H;Twyman-Saint Victor C;Cucolo L;Lee DSM;Pauken KE;Huang AC;Gangadhar TC;Amaravadi RK;Schuchter LM;Feldman MD;Ishwaran H;Vonderheide RH;Maity A;Wherry EJ;Minn AJ
通讯作者：
Minn AJ
影响因子：
3.7
作者：
Chacon JA;Wu RC;Sukhumalchandra P;Molldrem JJ;Sarnaik A;Pilon-Thomas S;Weber J;Hwu P;Radvanyi L
通讯作者：
Radvanyi L
DOI：
10.1038/nrc.2016.84
发表时间：
2016-09-23
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Nakazawa MS;Keith B;Simon MC
通讯作者：
Simon MC
DOI：
10.1158/1055-9965.epi-10-0565
发表时间：
2010-10
期刊：
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
影响因子：
--
作者：
Ma W;Wang M;Wang ZQ;Sun L;Graber D;Matthews J;Champlin R;Yi Q;Orlowski RZ;Kwak LW;Weber DM;Thomas SK;Shah J;Kornblau S;Davis RE
通讯作者：
Davis RE
DOI：
10.1073/pnas.1312570111
发表时间：
2014-02-18
影响因子：
11.1
作者：
Faubert, Brandon;Vincent, Emma E.;Jones, Russell G.
通讯作者：
Jones, Russell G.