Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy

被引：445

作者：

Cascone, Tina ^{[1
]}

McKenzie, Jodi A. ^{[2
,11
]}

Mbofung, Rina M. ^{[2
,12
]}

Punt, Simone ^{[2
]}

Wang, Zhe ^{[2
,13
]}

Xu, Chunyu ^{[2
]}

Williams, Leila J. ^{[2
]}

Wang, Zhiqiang ^{[3
]}

Bristow, Christopher A. ^{[4
]}

Carugo, Alessandro ^{[4
]}

Peoples, Michael D. ^{[4
]}

Li, Lerong ^{[5
]}

Karpinets, Tatiana ^{[6
]}

Huang, Lu ^{[2
]}

Malu, Shruti ^{[2
]}

Creasy, Caitlin ^{[2
]}

Leahey, Sara E. ^{[2
]}

Chen, Jiong ^{[7
]}

Chen, Yuan ^{[2
]}

Pelicano, Helen ^{[8
]}

Bernatchez, Chantale ^{[2
]}

Gopal, Y. N. Vashisht ^{[2
]}

Heffernan, Timothy P. ^{[4
]}

Hu, Jianhua ^{[7
]}

Wang, Jing ^{[5
]}

Amaria, Rodabe N. ^{[2
]}

Garraway, Levi A. ^{[9
,14
]}

Huang, Peng ^{[8
]}

Yang, Peiying ^{[10
]}

Wistuba, Ignacio I. ^{[8
]}

Woodman, Scott E. ^{[2
]}

Roszik, Jason ^{[2
,6
]}

Davis, R. Eric ^{[3
,8
]}

Davies, Michael A. ^{[2
]}

Heymach, John V. ^{[1
]}

Hwu, Patrick ^{[2
]}

Peng, Weiyi ^{[2
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77030 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA

[9] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[10] Univ Texas MD Anderson Canc Ctr, Dept Palliat Rehabil & Integrat Med, Houston, TX 77030 USA

[11] Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Houston, TX 77030 USA

[12] Merck Res Labs, Palo Alto, CA 94304 USA

[13] Springer Nat Nat Cell Biol, Shanghai 200000, Peoples R China

[14] Eli Lilly & Co, Indianapolis, IN 46285 USA

来源：

CELL METABOLISM | 2018年 / 27卷 / 05期

关键词：

LUNG-CANCER; BRAF INHIBITION; LACTIC-ACID; METABOLISM; MICROENVIRONMENT; IMMUNOTHERAPY; INFILTRATION; EXPRESSION; MELANOMA; SURVIVAL;

D O I：

10.1016/j.cmet.2018.02.024

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：977 / +

页数：15

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