Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy

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

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Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy

机译：增加的肿瘤糖酵解表征了对收养T细胞疗法的免疫抗性

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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.

机译：采用T细胞疗法（ACT）在某些癌症患者中产生耐用的反应;然而，大多数肿瘤是作用的难治性，并且潜在抗性的分子机制尚不清楚。使用两种独立方法，我们将肿瘤糖酵解鉴定为与黑色素瘤中免疫抗性相关的途径。将糖酵解相关基因上调在黑色素瘤和肺癌患者样品中被T细胞渗透不良渗透。糖酵解相关分子的过度表达损伤了肿瘤细胞的T细胞杀伤，而在体外和体内抑制糖酵解增强的T细胞介导的抗肿瘤免疫。此外，来自作用难治患者的黑色素组织中糖酵解相关的基因表达较高，衍生自这些患者的肿瘤细胞表现出较高的糖酵解活性。我们确定了在高糖酵解黑色素瘤细胞中的IRF1和CXCL10免疫刺激分子的降低。我们的研究结果表明，肿瘤糖酵解与作用的疗效相关，并鉴定糖酵解途径作为组合治疗干预的候选目标。

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《Cell metabolism》 |2018年第5期|共15页
作者
Cascone Tina; McKenzie Jodi A.; Mbofung Rina M.; Punt Simone; Wang Zhe; Xu Chunyu; Williams Leila J.; Wang Zhiqiang; Bristow Christopher A.; Carugo Alessandro; Peoples Michael D.; Li Lerong; Karpinets Tatiana; Huang Lu; Malu Shruti; Creasy Caitlin; Leahey Sara E.; Chen Jiong; Chen Yuan; Pelicano Helen; Bernatchez Chantale; Gopal Y. N. Vashisht; Heffernan Timothy P.; Hu Jianhua; Wang Jing; Amaria Rodabe N.; Garraway Levi A.; Huang Peng; Yang Peiying; Wistuba Ignacio I.; Woodman Scott E.; Roszik Jason; Davis R. Eric; Davies Michael A.; Heymach John V.; Hwu Patrick; Peng Weiyi;
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Univ Texas MD Anderson Canc Ctr Dept Thorac Head &

Neck Med Oncol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Melanoma Med Oncol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Melanoma Med Oncol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Melanoma Med Oncol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Melanoma Med Oncol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Melanoma Med Oncol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Melanoma Med Oncol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Lymphoma Myeloma Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Inst Appl Canc Sci Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Inst Appl Canc Sci Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Inst Appl Canc Sci Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Bioinformat &

Computat Biol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Genom Med Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Melanoma Med Oncol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Melanoma Med Oncol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Melanoma Med Oncol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Melanoma Med Oncol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Biostat Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Melanoma Med Oncol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Translat Mol Pathol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Melanoma Med Oncol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Melanoma Med Oncol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Inst Appl Canc Sci Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Biostat Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Bioinformat &

Computat Biol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Melanoma Med Oncol Houston TX 77030 USA;

Harvard Med Sch Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA;

Univ Texas MD Anderson Canc Ctr Dept Translat Mol Pathol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Palliat Rehabil &

Integrat Med Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Translat Mol Pathol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Melanoma Med Oncol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Melanoma Med Oncol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Lymphoma Myeloma Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Melanoma Med Oncol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Thorac Head &

Neck Med Oncol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Melanoma Med Oncol Houston TX 77030 USA;

Univ Texas MD Anderson Canc Ctr Dept Melanoma Med Oncol Houston TX 77030 USA;

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中图分类内分泌腺疾病及代谢病;
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专利

1. Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy [J] . Cascone Tina, McKenzie Jodi A., Mbofung Rina M., Cell metabolism . 2018,第5期

机译：增加的肿瘤糖酵解表征了对收养T细胞疗法的免疫抗性
2. Targeting Tumor Vasculature with TNF Leads Effector T Cells to the Tumor and Enhances Therapeutic Efficacy of Immune Checkpoint Blockers in Combination with Adoptive Cell Therapy [J] . Elia Angela Rita, Grioni Matteo, Basso Veronica, Clinical cancer research: an official journal of the American Association for Cancer Research . 2018,第9期

机译：用TNF引导肿瘤脉管系统导致肿瘤效应T细胞，并增强免疫检查点阻断剂的治疗功效与养殖细胞疗法组合
3. Depletion of CD4(+)CD25(high) regulatory T cells from tumor infiltrating lymphocytes predominantly induces Th1 type immune response in vivo which inhibits tumor growth in adoptive immunotherapy. [J] . Xu L, Xu W, Jiang Z, Cancer biology & therapy . 2009,第1期

机译：肿瘤浸润淋巴细胞中CD4（+）CD25（高）调节性T细胞的耗竭主要在体内诱导Th1型免疫反应，从而在过继免疫疗法中抑制肿瘤的生长。
4. Photodynamic therapy stimulates anti-tumor immune response in mouse models: the role of regulatory T-cells, anti-tumor antibodies, and immune attack on brain metastases [C] . Fatma Vatansever, Masayoshi Kawakubo, Hoon Chung, Biophotonics and immune responses VIII . 2013

机译：光动力疗法在小鼠模型中刺激抗肿瘤免疫反应：调节性T细胞，抗肿瘤抗体的作用以及对脑转移瘤的免疫攻击
5. The Immune Checkpoint B7x Promotes the Induction of Regulatory T Cells in the Tumor Microenvironment and Mediates Resistance to Immunotherapy [D] . John, Peter. 2022

机译：免疫检查点B7X促进肿瘤微环境中调节性T细胞的诱导，并介导对免疫疗法的抗性
6. Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T cell Therapy [O] . Tina Cascone, Jodi A. McKenzie, Rina M. Mbofung, -1

机译：肿瘤糖酵解增加表征对过继性T细胞疗法的免疫抵抗
7. Targeting Tumor Vasculature with TNF Leads Effector T Cells to the Tumor and Enhances Therapeutic Efficacy of Immune Checkpoint Blockers in Combination with Adoptive Cell Therapy [O] . Angela Rita Elia, Matteo Grioni, Veronica Basso, 2018

机译：用TNF引导肿瘤脉管系统导致肿瘤效应T细胞，并增强免疫检查点阻断剂的治疗功效与养殖细胞疗法组合
8. Adoptive Immunotherapy for Epithelial Ovarian Cancer Using T-cells Simultaneously Targeted to Tumor and Tumor-Associated Macrophages. [R] . Maher, J., Ghaem-Maghami, S. 2013

机译：上皮性卵巢癌的过继免疫治疗使用T细胞同时针对肿瘤和肿瘤相关的巨噬细胞。

Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy

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