Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer
| Autor: | Hannah Dada, Kristen E. Pauken, Rosemarie Mick, Amit Maity, Bihui Xu, Xiaowei Xu, Hemant Ishwaran, Tara C. Gangadhar, Christina Twyman-Saint Victor, Ramin S. Herati, Joseph L. Benci, Dana Patsch, Kathleen D. Mansfield, Andy J. Minn, Pamela M. Odorizzi, Andrew J. Rech, Ravi K. Amaravadi, Stephen M. Hahn, Ramesh Rengan, Lynn M. Schuchter, Michael Feldman, E. John Wherry, Daniel A. Pryma, Erietta Stelekati, Robert H. Vonderheide |
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| Rok vydání: | 2015 |
| Předmět: |
Cell cycle checkpoint
T-Lymphocytes Receptors Antigen T-Cell chemical and pharmacologic phenomena T-Lymphocytes Regulatory Article B7-H1 Antigen Mice 03 medical and health sciences 0302 clinical medicine Antigen medicine Animals Humans CTLA-4 Antigen Melanoma 030304 developmental biology Mice Inbred BALB C 0303 health sciences Multidisciplinary business.industry T-cell receptor Abscopal effect Cancer Cell Cycle Checkpoints medicine.disease 3. Good health Mice Inbred C57BL 030220 oncology & carcinogenesis Immunology Female business Checkpoint Blockade Immunotherapy CD8 |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/nature14292 |
| Popis: | 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 (Treg cells), thereby increasing the CD8 T-cell to Treg (CD8/Treg) 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/Treg 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. |
| Databáze: | OpenAIRE |
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