Cell Wall Skeleton

Abstract: Three kinds of morphologically distinct cell wall preparations were isolated from heat-killed Bifidobacterium infantis and examined for the relative antitumor efficacy with syngeneic Meth A fibrosarcoma in BALB/c mice. Ultrastructural examinations revealed that cell wall skeleton (CWS) did not retain morphologically recognizable cell wall structure but showed fibrous structure. By contrast, a new cell wall preparation, whole peptidoglycan (WPG), which was isolated from whole cells without being subjected to physically destructive methods, completely retained the intact cell wall structure. When WPG was disrupted by sonic treatment, it retained some degree of physical integrity of cell wall structure, as compared with CWS. The results of chemical analysis indicated that the three cell wall preparations had similar chemical properties. A single s.c. injection of either CWS, WPG, or sonicated WPG in a mixture with tumor cells resulted in a significant suppression of the tumor growth. They were of equally high activity. However, when WPG, sonicated WPG, or CWS was injected intralesionally five times into mice bearing 5-day-old tumors, the incidence of complete tumor regression was demonstrated to decrease in the order of 70, 40, and 20%, respectively. The in vitro cytotoxicity test excluded the possibility that the tumor cell destruction was the result of direct cytotoxicity of the cell wall preparations. From these findings, it was concluded that WPG was an active stimulator of host-mediated response at the tumor-growing sites.

Abstract: Purpose: We developed an effective immunotherapy, which could induce antitumor immune responses against shared and unique tumor antigens expressed in autologous tumors. Experimental Design: 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.