title: Mechanisms involved in radiation enhancement of intratumoral dendritic cell therapy.
abstract: We have previously reported that local tumor irradiation, without inducing cell death, can augment the therapeutic efficacy of intratumoral (IT) dendritic cell (DC) vaccination. This study examined potential mechanisms underlying radiation enhancement of IT DC therapy in this setting. Even though ionizing radiation did not mediate tumor cell killing, bone marrow-derived DCs acquired in vitro tumor antigens from irradiated D5 murine melanoma cells more efficiently than from untreated cells. This radiation-enhanced loading of DCs did not induce DC maturation, but was associated with improved cross-priming of T cells both in vitro and in vivo. Furthermore, in vivo pulsing of DCs with irradiated versus untreated tumor cells resulted in superior presentation of tumor antigens to T cells. In addition, tumor irradiation facilitated homing of IT administered DCs to the draining lymph node, possibly by down-regulating CCL21 expression within the tumor mass. Studies of the tumor microenvironment in irradiated versus untreated tumors did not reveal significant inflammatory changes. Moreover, radiation did not promote accumulation of CD4 or CD8 effector T cells within solid tumors. Our results indicate that, without inducing cytotoxicity, tumor irradiation can enhance the ability of DCs to capture tumor antigens, migrate to the draining lymph node, and present processed antigens to T cells. These findings may prove useful in designing future strategies for human cancer immunotherapy.
authors.affiliation: Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, USA.
authors.forename: Seagal
authors.initials: S
authors.lastname: Teitz-Tennenbaum
authors.forename: Qiao
authors.initials: Q
authors.lastname: Li
authors.forename: Ryuji
authors.initials: R
authors.lastname: Okuyama
authors.forename: Mary A
authors.initials: MA
authors.lastname: Davis
authors.forename: Rong
authors.initials: R
authors.lastname: Sun
authors.forename: Joel
authors.initials: J
authors.lastname: Whitfield
authors.forename: Randall N
authors.initials: RN
authors.lastname: Knibbs
authors.forename: Lloyd M
authors.initials: LM
authors.lastname: Stoolman
authors.forename: Alfred E
authors.initials: AE
authors.lastname: Chang
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000528:radiation effects; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000528:radiation effects* / Q000627:therapeutic use; D002465:Cell Movement / Q000528:radiation effects*; D054421:Chemokine CCL21 / Q000276:immunology / Q000378:metabolism; D045142:Cross-Priming / Q000528:radiation effects; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000528:radiation effects*; D005452:Fluoresceins; D006801:Humans; D016219:Immunotherapy, Adoptive; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D008822:Mice, Transgenic; D011839:Radiation, Ionizing; D013388:Succinimides; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D054421:Chemokine CCL21; D005452:Fluoresceins; D013388:Succinimides