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Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer

机译：辐射和双重检查点封锁激活了癌症的非冗余免疫机制

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摘要

Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T-cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires radiation, anti-CTLA4 and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T-regulatory cells (T_(reg) cells), thereby increasing the CD8 T-cell to T_(reg) (CD8/T_(reg)) ratio. Radiation enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while radiation shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T-cell exhaustion to mitigate depression in the CD8/T_(reg) ratio and further encourages oligoclonal T-cell expansion. Similarly to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T-cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumours to escape anti-CTLA4-based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms.
机译：免疫检查点抑制剂可产生令人印象深刻的临床反应，但要达到最佳效果，则需要相互结合以及其他疗法。这就提出了有关非冗余和抵制机制的基本问题。在这里，我们报告了使用抗CTLA4抗体（抗CTLA4）和放射治疗的转移性黑色素瘤患者亚群中的主要肿瘤消退，并在小鼠模型中重现了这种效应。尽管联合治疗可改善照射和未照射肿瘤的反应，但耐药性很常见。对小鼠的公正分析表明，耐药性是由于黑色素瘤细胞上PD-L1的上调引起的，并且与T细胞衰竭有关。因此，黑素瘤和其他癌症类型的最佳反应需要放疗，抗CTLA4和抗PD-L1 / PD-1。抗CTLA4主要抑制T调节细胞（T_reg细胞），从而增加CD8 T细胞与T_reg的比率（CD8 / T_reg）。辐射增强了肿瘤内T细胞的T细胞受体（TCR）库的多样性。在一起，抗CTLA4会促进T细胞的扩增，而放射线会影响扩展的外周克隆的TCR库。添加PD-L1阻滞剂可逆转T细胞衰竭，以减轻CD8 / T_（reg）比值的降低，并进一步促进寡克隆T细胞扩增。与小鼠的结果相似，我们的黑色素瘤临床试验患者显示高PD-L1对放射线加抗CTLA4无反应，表现出持续性T细胞衰竭，并且进展迅速。因此，黑色素瘤细胞上的PD-L1可使肿瘤逃脱基于抗CTLA4的疗法，并且放射线，抗CTLA4和抗PD-L1的组合可通过不同的机制促进反应和免疫力。

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  • 来源
    《Nature》 |2015年第7547期|373-377|共5页
  • 作者

    Christina Twyman-Saint Victor; Andrew J. Rech; Amit Maity; Ramesh Rengan; Kristen E. Pauken; Erietta Stelekati; Joseph L. Benci; Bihui Xu; Hannah Dada; Pamela M. Odorizzi; Ramin S. Herati; Kathleen D. Mansfield; Dana Patsch; Ravi K. Amaravadi; Lynn M. Schuchter; Hemant Ishwaran; Rosemarie Mick; Daniel A. Pryma; Xiaowei Xu; Michael D. Feldman; Tara C. Gangadhar; Stephen M. Hahn; E. John Wherry; Robert H. Vonderheide; Andy J. Minn;

  • 作者单位

    Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Departmentof Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Departmentof Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Department of Radiation Oncology, University of Washington School of Medicine, Washington 98195, USA;

    Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Departmentof Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Departmentof Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Departmentof Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Departmentof Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Division of Biostatistics, Department of Public Health Sciences, University of Miami, Miami, Florida 33136, USA;

    Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Department of Pathologyand Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Department of Pathologyand Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Departmentof Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;

    Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Departmentof Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

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