Molecular mechanisms underlying the modulation of T-cell proliferation and cytotoxicity by immobilized CCL21 and ICAM1

Abstract

A major challenge in adoptive cancer immunotherapy is the effective balance between the proliferation and cytotoxic capacity of effector CD8+ T cells. In this study, we explored the molecular mechanisms through which a "synthetic immune niche" (SIN), composed of immobilized CCL21 and ICAM1, modulates the interplay between these two cellular properties. Temporal phenotypic profiling of OVA-specific murine T cells revealed major differences in the response to SIN stimulation following antigen-specific and nonspecific activation. Thus, SIN treatment enhanced both the expansion and cytotoxicity of cells activated by OVA-loaded DCs on day 4, while similar treatment of cells activated by anti-CD3/CD28-conjugated beads dramatically enhanced cell expansion but unexpectedly blocked their cytotoxicity, which fully recovered only on day 7. Molecular profiling suggested that upregulation of cytotoxic gene signatures drives the SIN effect following DC activation, while downregulation of exhaustion and proapoptotic genes optimizes the proliferation-cytotoxicity balance in bead-activated cells.