Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy

Publication date: Available online 5 April 2018
Source:Cell Metabolism
Author(s): Tina Cascone, Jodi A. McKenzie, Rina M. Mbofung, Simone Punt, Zhe Wang, Chunyu Xu, Leila J. Williams, Zhiqiang Wang, Christopher A. Bristow, Alessandro Carugo, Michael D. Peoples, Lerong Li, Tatiana Karpinets, Lu Huang, Shruti Malu, Caitlin Creasy, Sara E. Leahey, Jiong Chen, Yuan Chen, Helen Pelicano, Chantale Bernatchez, Y.N. Vashisht Gopal, Timothy P. Heffernan, Jianhua Hu, Jing Wang, Rodabe N. Amaria, Levi A. Garraway, Peng Huang, Peiying Yang, Ignacio I. Wistuba, Scott E. Woodman, Jason Roszik, R. Eric Davis, Michael A. Davies, John V. Heymach, Patrick Hwu, Weiyi Peng
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.

Graphical abstract

Teaser

Cascone 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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