Radiation-induced apoptosis along with local and systemic cytokine elaboration is associated with DC plus radiotherapy-mediated renal cell tumor regression.
Utilizing melanoma and sarcoma tumor models syngeneic to C57BL/6 mice, we previously reported the antitumor effects of intratumoral (i.t.) administration of dendritic cells (DC) combined with localized radiotherapy (RT). However, the mechanisms underlying the augmented therapeutic effects have yet to be fully defined. Using the BALB/c host, we explored in this study the capacity of RT to augment the therapeutic efficacy of DC in the syngeneic renal cell cancer, Renca. I.t. DC administration combined with RT inhibited tumor growth in a synergistic manner. This extends our previous findings using a different host strain and two histologically distinct tumor models. More importantly, we provide evidence in this report that RT induced significant apoptosis and necrosis in Renca tumor cells, which involved down-regulated expression of Bcl-2 and a concurrent up-regulated expression of Bax. We also found significantly elevated expression of TNFalpha in RT plus DC-treated Renca tumors. Furthermore, splenocytes isolated from DC plus RT-treated mice elaborated higher levels of IL-2, IL-4, IFNgamma and IgG, IgM in response to tumor cells compared with splenocytes from monotherapy-treated hosts. These data support the conclusion that radiotherapy enhanced DC vaccination by inducing tumor cell apoptosis in BABL/c host, and the significantly augmented therapeutic efficacy by RT+DC treatment was associated with an increased local production of TNFalpha as well as an amplified systemic antitumor responses conferred by the combined therapy. I.t. DC administration in concert with localized RT may represent a promising novel regimen for human cancer therapy.
Huang
Jianhua
J
Department of Immunology, The PLA General Hospital, Beijing, China, and Division of Surgical Oncology, University of Michigan, Ann Arbor 48109-0666, USA.
Wang
Yao
Y
Guo
Jia
J
Lu
Haiyan
H
Lin
Xingshi
X
Ma
Lin
L
Teitz-Tennenbaum
Seagal
S
Chang
Alfred E
AE
Li
Qiao
Q
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000528:radiation effects; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002454:Cell Differentiation / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism / Q000637:transplantation*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D007074:Immunoglobulin G / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism; D016219:Immunotherapy, Adoptive; D015847:Interleukin-4 / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011878:Radiotherapy; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D015703:Antigens, CD; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D016207:Cytokines; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D016179:Granulocyte Colony-Stimulating Factor; D015847:Interleukin-4