PD-1 blockade reverts motility arrest of transferred tumor-infiltrating CD8+ T cells in adoptive cell transfer immunotherapy (TUM7P.1014)

Abstract

Abstract Adoptive cell transfer (ACT) immunotherapy can result in complete responses in the treatment of metastatic solid cancers, however the majority of patients eventually progress. Although many immune regulatory programs are context-dependent, the in vivo behavior of adoptively-transferred CD8+ T cells over time remains unknown. Using the Pmel-1 model, we performed intravital microscopy of subcutaneous tumors in mice to visualize the in vivo motility of transferred tumor-specific CD8+ T cells. This revealed that CD8+ T cell motility arrest increased over time after adoptive transfer. By ex vivo analyses, behavioral change coincided with a reduction in IFN-γ production and glucose uptake. As the transferred cells strongly expressed PD-1, we treated mice with both ACT and anti-PD-1 blocking antibody to determine the effect of immune checkpoint blockade on cellular motility. In mice treated with anti-PD-1 blocking antibody, transferred intratumoral CD8+ T cell motility arrest diminished, as compared with controls. This corresponded with an increase in CD8+ T cell glucose uptake. These data demonstrate that intratumoral CD8+ T cell behavior in ACT is dynamic and that greater motility is associated with increased functionality and bioenergetic demand. Furthermore, concurrent PD-1 blockade exerts a cell-intrinsic effect on transferred CD8+ T cells suggesting synergy between ACT and anti-PD-1 immunotherapy and the potential for their combinatorial use in the treatment of cancer