RESUMEN
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+CD38hi 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+CD38hi 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+CD38hi CD8+ cells that is reversed by optimal priming. PD-1+CD38hi 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.
Asunto(s)
ADP-Ribosil Ciclasa 1/metabolismo , Linfocitos T CD8-positivos/inmunología , Resistencia a Antineoplásicos/inmunología , Glicoproteínas de Membrana/metabolismo , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/inmunología , ADP-Ribosil Ciclasa 1/genética , Animales , Anticuerpos/inmunología , Linfocitos T CD8-positivos/patología , Vacunas contra el Cáncer/inmunología , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Inmunoterapia/métodos , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Microambiente Tumoral/inmunologíaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.