| First Author | Verma V | Year | 2019 |
| Journal | Nat Immunol | Volume | 20 |
| Issue | 9 | Pages | 1231-1243 |
| PubMed ID | 31358999 | Mgi Jnum | J:324332 |
| Mgi Id | MGI:6711322 | Doi | 10.1038/s41590-019-0441-y |
| Citation | Verma V, et al. (2019) PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1(+)CD38(hi) cells and anti-PD-1 resistance. Nat Immunol 20(9):1231-1243 |
| abstractText | Understanding resistance to antibody to programmed cell death protein 1 (PD-1; anti-PD-1) is crucial for the development of reversal strategies. In anti-PD-1-resistant models, simultaneous anti-PD-1 and vaccine therapy reversed resistance, while PD-1 blockade before antigen priming abolished therapeutic outcomes. This was due to induction of dysfunctional PD-1(+)CD38(hi) CD8(+) cells by PD-1 blockade in suboptimally primed CD8 cell conditions induced by tumors. This results in erroneous T cell receptor signaling and unresponsiveness to antigenic restimulation. On the other hand, PD-1 blockade of optimally primed CD8 cells prevented the induction of dysfunctional CD8 cells, reversing resistance. Depleting PD-1(+)CD38(hi) CD8(+) cells enhanced therapeutic outcomes. Furthermore, non-responding patients showed more PD-1(+)CD38(+)CD8(+) cells in tumor and blood than responders. In conclusion, the status of CD8(+) T cell priming is a major contributor to anti-PD-1 therapeutic resistance. PD-1 blockade in unprimed or suboptimally primed CD8 cells induces resistance through the induction of PD-1(+)CD38(hi) CD8(+) cells that is reversed by optimal priming. PD-1(+)CD38(hi) CD8(+) cells serve as a predictive and therapeutic biomarker for anti-PD-1 treatment. Sequencing of anti-PD-1 and vaccine is crucial for successful therapy. |
