Non-conventional Inhibitory CD4(+)Foxp3(-)PD-1(hi) T Cells as a Biomarker of Immune Checkpoint Blockade Activity

Zappasodi Roberta; Budhu Sadna; Hellmann Matthew D.; Postow Michael A.; Senbabaoglu Yasin; Manne Sasikanth; Gasmi Billel; Liu Cailian; Zhong Hong; Li Yanyun; Huang Alexander C.; Hirschhorn-Cymerman Daniel; Panageas Katherine S.; Wherry E. John; Merghoub Taha; Wolchok Jedd D.

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Non-conventional Inhibitory CD4(+)Foxp3(-)PD-1(hi) T Cells as a Biomarker of Immune Checkpoint Blockade Activity

机译：非常规抑制CD4（+）FOXP3（ - ）PD-1（HI）T细胞作为免疫检查点延迟活动的生物标志物

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A significant proportion of cancer patients do not respond to immune checkpoint blockade. To better understand the molecular mechanisms underlying these treatments, we explored the role of CD4(+)Foxp3(-) T cells expressing PD-1 (4PD1(hi)) and observed that 4PD1(hi) hi accumulate intratumorally as a function of tumor burden. Interestingly, CTLA-4 blockade promotes intratumoral and peripheral 4PD1(hi) increases in a dose-dependent manner, while combination with PD-1 blockade mitigates this effect and improves anti-tumor activity. We found that lack of effective 4PD1(hi) reduction after anti-PD-1 correlates with poor prognosis. Mechanistically, we provide evidence that mouse and human circulating and intra-tumor 4PD1(hi) inhibit T cell functions in a PD-1/PD-L1 dependent fashion and resemble follicular helper T cell (T-FH)-like cells. Accordingly, anti-CTLA-4 activity is improved in TFH deficient mice.

机译：大量比例的癌症患者不响应免疫检查点延迟。为了更好地了解这些处理的潜在的分子机制，我们探讨了表达PD-1（4PD1（HI））的CD4（+）Foxp3（ - ）T细胞的作用，并观察到4pd1（Hi）Hi作为肿瘤的函数划分的纵横体积负担。有趣的是，CTLA-4阻断促进肿瘤内和外周4PD1（HI）以剂量依赖性方式增加，同时与PD-1阻断的组合减轻这种效果并改善抗肿瘤活性。抗PD-1与预后差相关后，我们发现缺乏有效的4PD1（HI）降低。机械地，我们提供了小鼠和人循环和肿瘤内4PD1（HI）以PD-1 / Pd-L1依赖性方式抑制T细胞功能的证据，类似于卵泡辅助T细胞（T-FH） - 状细胞。因此，TFH缺陷小鼠中抗CTLA-4活性得到改善。

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《Cancer Cell》 |2018年第6期|共23页
作者
Zappasodi Roberta; Budhu Sadna; Hellmann Matthew D.; Postow Michael A.; Senbabaoglu Yasin; Manne Sasikanth; Gasmi Billel; Liu Cailian; Zhong Hong; Li Yanyun; Huang Alexander C.; Hirschhorn-Cymerman Daniel; Panageas Katherine S.; Wherry E. John; Merghoub Taha; Wolchok Jedd D.;
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Mem Sloan Kettering Canc Ctr Ludwig Collaborat New York NY 10065 USA;

Mem Sloan Kettering Canc Ctr Ludwig Collaborat New York NY 10065 USA;

Mem Sloan Kettering Canc Ctr Parker Inst Canc Immunotherapy New York NY 10065 USA;

Mem Sloan Kettering Canc Ctr Dept Med New York NY 10065 USA;

Mem Sloan Kettering Canc Ctr Ludwig Collaborat New York NY 10065 USA;

Univ Penn Perelman Sch Med Dept Microbiol Philadelphia PA 19104 USA;

Mem Sloan Kettering Canc Ctr Ludwig Collaborat New York NY 10065 USA;

Mem Sloan Kettering Canc Ctr Ludwig Collaborat New York NY 10065 USA;

Mem Sloan Kettering Canc Ctr Ludwig Collaborat New York NY 10065 USA;

Mem Sloan Kettering Canc Ctr Ludwig Collaborat New York NY 10065 USA;

Mem Sloan Kettering Canc Ctr Parker Inst Canc Immunotherapy New York NY 10065 USA;

Mem Sloan Kettering Canc Ctr Ludwig Collaborat New York NY 10065 USA;

Mem Sloan Kettering Canc Ctr Epidemiol &

Biostat New York NY 10065 USA;

Mem Sloan Kettering Canc Ctr Parker Inst Canc Immunotherapy New York NY 10065 USA;

Mem Sloan Kettering Canc Ctr Ludwig Collaborat New York NY 10065 USA;

Mem Sloan Kettering Canc Ctr Ludwig Collaborat New York NY 10065 USA;

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正文语种 eng
中图分类肿瘤学;
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专利

1. Non-conventional Inhibitory CD4(+)Foxp3(-)PD-1(hi) T Cells as a Biomarker of Immune Checkpoint Blockade Activity (vol 33, pg 1017, 2018) [J] . Zappasodi Roberta, Budhu Sadna, Hellmann Matthew D., Cancer Cell . 2018,第4期

机译：非常规抑制CD4（+）FOXP3（ - ）PD-1（HI）T细胞作为免疫检查点延迟活动的生物标志物（Vol 33，PG 1017，2018）
2. Dual PD-1 and CTLA-4 Checkpoint Blockade Promotes Antitumor Immune Responses through CD4(+)Foxp3(-) Cell-Mediated Modulation of CD103(+) Dendritic Cells [J] . Beavis Paul A., Henderson Melissa A., Giuffrida Lauren, Cancer immunology research. . 2018,第9期

机译：双PD-1和CTLA-4检查点梗死通过CD4（+）Foxp3（ - ）细胞介导的CD103（+）树突细胞调节抗肿瘤免疫应答
3. Preclinical activity and pharmacodynamic biomarkers of W014A, a PD-1 decoy peptide blocking both PD-1 immune checkpoint ligands, PD-L1 and PD-L2 [J] . Bailly C., Broussas M., Sasikumar P. G., European journal of cancer: official journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR) . 2014,第Suppla6期

机译：W014A（一种阻断PD-1免疫检查点配体，PD-L1和PD-L2的PD-1诱饵肽）的临床前活性和药理生物标志物
4. Molecular dynamics of the immune checkpoint Programmed Cell Death Protein I, PD-1: Conformational changes of the BC-loop upon binding of the ligand PD-L1 and the monoclonal antibody nivolumab [C] . Bernhard Roither, Chris Oostenbrink, Wolfgang Schreiner IEEE International Conference on Bioinformatics and Biomedicine . 2019

机译：免疫检查点的分子动力学程序性细胞死亡蛋白I，PD-1：配体PD-L1与单克隆抗体nivolumab结合后BC环的构象变化
5. T Cell Function and PD-1 Checkpoint Blockade in Tumor Progression [D] . Wang, Ziming. 2019

机译：T细胞功能和PD-1检查点延迟肿瘤进展
6. Non-conventional inhibitory CD4+Foxp3−PD-1hi T cells as a biomarker of immune checkpoint blockade activity [O] . Roberta Zappasodi, Sadna Budhu, Matthew D. Hellmann, -1

机译：非常规抑制性CD4 + Foxp3-PD-1hi T细胞可作为免疫检查点阻断活性的生物标志物
7. Breast Cancer Cells and PD-1/PD-L1 Blockade Upregulate the Expression of PD-1, CTLA-4, TIM-3 and LAG-3 Immune Checkpoints in CD4+ T Cells [O] . 2019

机译：乳腺癌细胞和PD-1 / PD-L1阻断上调了CD4 + T细胞中PD-1，CTLA-4，TIM-3和LAG-3免疫检查点的表达

Non-conventional Inhibitory CD4(+)Foxp3(-)PD-1(hi) T Cells as a Biomarker of Immune Checkpoint Blockade Activity

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