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.
Author Info: (1) Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Osaka 584-8540, Japan. (2) Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani Uni
Author Info: (1) Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Osaka 584-8540, Japan. (2) Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Osaka 584-8540, Japan. (3) Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Osaka 584-8540, Japan. (4) Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Graduate school of Medicine, Wakayama, Wakayama 641-8509, Japan. (5) Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Graduate school of Medicine, Wakayama, Wakayama 641-8509, Japan. (6) Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda City Chiba 278-0022, Japan. (7) Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Osaka 584-8540, Japan. Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan. (8) Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Osaka 584-8540, Japan. (9) Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Osaka 584-8540, Japan. (10) Department of Dermatology, Kyoto University, Graduate School of Medicine, Sakyou-ku, Kyoto 606-8507, Japan. (11) Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda City Chiba 278-0022, Japan. (12) Department of Dermatology, Kyoto University, Graduate School of Medicine, Sakyou-ku, Kyoto 606-8507, Japan. (13) Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Osaka 584-8540, Japan. (14) Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Osaka 584-8540, Japan. (15) Immunology Theme, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia. School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales Sydney, Kensington, NSW 2033 Australia. (16) Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Osaka 584-8540, Japan.
