RT Journal Article
SR Electronic
T1 Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 813584
DO 10.1101/813584
A1 Alok Kumar
A1 Kenji Chamoto
A1 Partha S. Chowdhury
A1 Tasuku Honjo
YR 2019
UL http://biorxiv.org/content/early/2019/10/21/813584.abstract
AB 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 which inhibited T cell proliferation and mitochondrial activation. 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 to B16, which employs immune ignorance. These results demonstrated that our ‘bilateral tumor model’ was useful for stratifying tumors to investigate the mechanism of unresponsiveness and develop strategy for proper combination therapy.