4.6 Article

Suppression of murine tumour growth through CD8+ cytotoxic T lymphocytes via activated DEC-205+ dendritic cells by sequential administration of -galactosylceramide in vivo

Journal

IMMUNOLOGY
Volume 151, Issue 3, Pages 324-339

Publisher

WILEY
DOI: 10.1111/imm.12733

Keywords

co-stimulatory molecule; cytotoxic T lymphocytes; tumour-infiltrating dendritic cells; tumour-infiltrating lymphocytes; -galactosylceramide

Categories

Funding

  1. Ministry of Education, Science, Sport, and Culture
  2. Ministry of Health and Labor and Welfare, Japan [25461715]
  3. Japanese Health Sciences Foundation
  4. Promotion and Mutual Aid Corporation for Private Schools of Japan
  5. MEXT-Programme for the Strategic Research Foundation at Private Universities, Japan
  6. Grants-in-Aid for Scientific Research [16K09262, 25461715] Funding Source: KAKEN

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Cancer immunity is mediated through the effective priming and activation of tumour-specific class I MHC molecule-restricted CD8(+) cytotoxic T lymphocytes (CTLs). DEC-205(+) dendritic cells (DCs) can cross-present the epitope(s) of captured tumour antigens associated with class I MHC molecules alongside co-stimulatory molecules to prime and activate tumour-specific CD8(+) CTLs. Immunosuppressive tolerogenic DCs with reduced co-stimulatory molecules may be a cause of impaired CTL induction. Hepa1-6-1 cells were established from the mouse hepatoma cell line Hepa1-6; these cells grow continuously after subcutaneous implantation into syngeneic C57BL/6 (B6) mice and do not prime CD8(+) CTLs. In this study, we show that the growth of ongoing tumours was suppressed by activated CD8(+) CTLs with tumour-specific cytotoxicity through the administration of the glycolipid -galactosylceramide (-GalCer), which is a compound known to stimulate invariant natural killer T (iNKT) cells and selectively activate DEC-205(+) DCs. Moreover, we demonstrated that sequential repetitive intraperitoneal inoculation with -GalCer every 48 hr appeared to convert tolerogenic DEC-205(+) DCs into immunogenic DCs with a higher expression of co-stimulatory molecules and a stronger cross-presentation capacity, which primed CTL precursors and induced tumour-specific CD8(+) CTLs within the tumour environment without activating iNKT cells. These findings provide a new basis for cancer immunotherapy to convert tolerogenic DEC-205(+) DCs within tumours into immunogenic DCs through the sequential administration of an immuno-potent lipid/glycolipid, and then activated immunogenic DCs with sufficient expression of co-stimulatory molecules prime and activate tumour-specific CD8(+) CTLs within the tumour to control tumour growth.

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