eLife | |
Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy | |
Partha S Chowdhury1  Tasuku Honjo1  Alok Kumar1  Kenji Chamoto1  | |
[1] Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan; | |
关键词: cancer immunotherapy; energy metabolism; systemic immunosuppression; immune resistance; oxygen consumption rate; combination therapy; Mouse; | |
DOI : 10.7554/eLife.52330 | |
来源: publisher | |
【 摘 要 】
PD-1 blockade therapy has revolutionized cancer treatments. However, a substantial population of patients is unresponsive. To rescue unresponsive patients, the mechanism of unresponsiveness to PD-1 blockade therapy must be elucidated. Using a ‘bilateral tumor model’ where responsive and unresponsive tumors were inoculated into different sides of the mouse belly, we demonstrated that unresponsive tumors can be categorized into two groups: with and without systemic immunosuppressive property (SIP). The SIP-positive tumors released uncharacterized, non-proteinaceous small molecules that inhibited mitochondrial activation and T cell proliferation. By contrast, the SIP-negative B16 tumor escaped from immunity by losing MHC class I expression. Unresponsiveness of SIP-positive tumors was partially overcome by improving the mitochondrial function with a mitochondrial activator; this was not successful for B16, which employs immune ignorance. These results demonstrated that the ‘bilateral tumor model’ was useful for stratifying tumors to investigate the mechanism of unresponsiveness and develop a strategy for proper combination therapy.
【 授权许可】
CC BY
【 预 览 】
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RO202004216335319ZK.pdf | 2056KB | download |