Enhancement of immunologic tumor regression by intratumoral administration of dendritic cells in combination with cryoablative tumor pretreatment and Bacillus Calmette-Guerin cell wall skeleton stimulation.
OBJECTIVE
We developed an effective immunotherapy, which could induce antitumor immune responses against shared and unique tumor antigens expressed in autologous tumors.


METHODS
Intratumoral administration of dendritic cells is one of the individualized immunotherapies; however, the antitumor activity is relatively weak. In this study, we attempted to enhance the antitumor efficacy of the i.t. dendritic cell administration by combining dendritic cells stimulated with Bacillus Calmette-Guerin cell wall skeleton (BCG-CWS) additionally with cryoablative pretreatment of tumors and analyzed the therapeutic mechanisms.


RESULTS
These two modifications (cryoablation of tumors and BCG-CWS stimulation of dendritic cells) significantly increases the antitumor effect on both the treated tumor and the untreated tumor, which was distant at the opposite side, in a bilateral s.c. murine CT26 colon cancer model. Further analysis of the augmented antitumor effects revealed that the cryoablative pretreatment enhances the uptake of tumor antigens by the introduced dendritic cells, resulting in the induction of tumor-specific CD8(+) T cells responsible for the in vivo tumor regression of both treated and remote untreated tumors. This novel combination i.t. dendritic cell immunotherapy was effective against well-established large tumors. The antitumor efficacy was further enhanced by depletion of CD4(+)CD25(+)FoxP3(+) regulatory T cells.


CONCLUSIONS
This novel dendritic cell immunotherapy with i.t. administration of BCG-CWS-treated dendritic cells following tumor cryoablation could be used for the therapy of cancer patients with multiple metastases.
Udagawa
Masaru
M
Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.
Kudo-Saito
Chie
C
Hasegawa
Go
G
Yano
Kazuhito
K
Yamamoto
Aiko
A
Yaguchi
Masae
M
Toda
Masahiro
M
Azuma
Ichiro
I
Iwai
Takehisa
T
Kawakami
Yutaka
Y
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D001500:BCG Vaccine / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D017358:Cell Wall Skeleton / Q000276:immunology; D003110:Colonic Neoplasms / Q000601:surgery / Q000628:therapy*; D003131:Combined Modality Therapy; D003452:Cryosurgery / Q000379:methods*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D007111:Immunity, Cellular; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000502:physiology; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; D017358:Cell Wall Skeleton; D009363:Neoplasm Proteins