Moriya et al. induced immunogenic cell death (ICD) in diphtheria toxin (DT) receptor-positive tumor cells by administering DT to tumor-bearing mice. They used KikGR knock-in mice (a photolabeling enabling protein) to study in vivo non-tumor cell activity and trafficking. ICD promoted tumor infiltration and phagocytosis by DCs, DC migration (mediated by DAMP, CCR7, and S1PR1-activated pathways) to draining lymph nodes (dLN), increased proliferation of tumor-specific CD8+ cells, and suppression of secondary tumor growth. LPS induced more total DC (but not CD103+ DC) migration than did ICD, but LPS did not enhance proliferation of tumor-specific CD8+ cells.
Contributed by Margot O’Toole
ABSTRACT: Immunogenic tumor cell death enhances anti-tumor immunity. However, the mechanisms underlying this effect are incompletely understood. We established a system to induce tumor cell death in situ and investigated its effect on dendritic cell (DC) migration and T cell responses using intravital photolabeling in mice expressing KikGR photoconvertible protein. We demonstrate that tumor cell death induces phagocytosis of tumor cells by tumor-infiltrating (Ti)-DCs, and HMGB1-TLR4 and ATP-P2X7 receptor signaling-dependent Ti-DC emigration to draining lymph nodes (dLNs). This led to an increase in anti-tumor CD8(+) T cells of memory precursor effector phenotype and secondary tumor growth inhibition in a CD103(+) DC-dependent manner. However, combining tumor cell death induction with lipopolysaccharide treatment stimulated Ti-DC maturation and emigration to dLNs but did not improve tumor immunity. Thus, immunogenic tumor cell death enhances tumor immunity by increasing Ti-DC migration to dLNs where they promote anti-tumor T cell responses and tumor growth inhibition.