RESUMEN
The maintenance of antigen-specific CD8+ T cells underlies the efficacy of vaccines and immunotherapies. Pathways contributing to CD8+ T cell loss are not completely understood. Uncovering the pathways underlying the limited persistence of CD8+ T cells would be of significant benefit for developing novel strategies of promoting T cell persistence. Here, we demonstrate that murine CD8+ T cells experience endoplasmic reticulum (ER) stress following activation and that the ER-associated degradation (ERAD) adapter Sel1L is induced in activated CD8+ T cells. Sel1L loss limits CD8+ T cell function and memory formation following acute viral infection. Mechanistically, Sel1L is required for optimal bioenergetics and c-Myc expression. Finally, we demonstrate that human CD8+ T cells experience ER stress upon activation and that ER stress is negatively associated with improved T cell functionality in T cell-redirecting therapies. Together, these results demonstrate that ER stress and ERAD are important regulators of T cell function and persistence.
Asunto(s)
Linfocitos T CD8-positivos , Estrés del Retículo Endoplásmico , Degradación Asociada con el Retículo Endoplásmico , Memoria Inmunológica , Animales , Humanos , Ratones , Enfermedad Aguda , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/virología , Coriomeningitis Linfocítica/patología , Ratones Endogámicos C57BL , Proteínas , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Masculino , FemeninoRESUMEN
T cells use highly diverse receptors (TCRs) to identify tumor cells presenting neoantigens arising from genetic mutations and establish anti-tumor activity. Immunotherapy harnessing neoantigen-specific T cells to target tumors has emerged as a promising clinical approach. To assess whether a comprehensive peripheral mononuclear blood cell analysis predicts responses to a personalized neoantigen cancer vaccine combined with anti-PD-1 therapy, we characterize the TCR repertoires and T and B cell frequencies in 21 patients with metastatic melanoma who received this regimen. TCR-α/ß-chain sequencing reveals that prolonged progression-free survival (PFS) is strongly associated with increased clonal baseline TCR repertoires and longitudinal repertoire stability. Furthermore, the frequencies of antigen-experienced T and B cells in the peripheral blood correlate with repertoire characteristics. Analysis of these baseline immune features enables prediction of PFS following treatment. This method offers a pragmatic clinical approach to assess patients' immune state and to direct therapeutic decision making.