Abstract
Doxorubicin (DXR) has been reported to have direct cytotoxicity against cancer cells and indirect immunotoxicity by modulation of host antitumor immunity. Hence, it may prevent cancer progression by a dual mechanism. Doxil®, a formulation of DXR encapsulated in polyethylene glycol modified (PEGylated) liposomes, is the most widely used of the clinically approved liposomal anticancer drugs. However, the effect of Doxil® on host antitumor immunity is not well understood. In this study, Doxil® efficiently suppressed tumor growth in immunocompetent mice bearing C26 murine colorectal carcinomas, but not in T cell-deficient nude mice, indicating a contribution of T cells to the overall antitumor effect of Doxil®. In immunocompetent mice, Doxil® increased major histocompatibility complex (MHC-1) levels in C26 tumors, which may be an indicator of increased immunogenicity of tumor cells, and potentially amplified tumor immunogenicity by decreasing immunosuppressive cells such as regulatory T cells, tumor-associated microphages and myeloid-derived suppressor cells that collectively suppress T cell-mediated antitumor responses. This suggests that encapsulation of DXR into PEGylated liposomes increased the therapeutic efficacy of DXR though effects on host antitumor immunogenicity in addition to direct cytotoxic effects on tumor cells. This report describes the role of host antitumor immunity in the overall therapeutic effects of Doxil®. Manipulating pharmacokinetics and biodistribution of chemotherapeutic agents with immunomodulatory properties may increase their therapeutic efficacies by amplifying host antitumor immunity in addition to direct cytotoxic effects on tumor cells.
Highlights
Chemotherapy using cytotoxic chemicals to induce cell death, despite recent advances in alternative therapies, remains a frontline defense against malignant tumors
Aoto et al [7] reported that treatment with chemotherapeutic agents could trigger the release of the high-mobility group box 1 protein (HMGB1), a toll-like receptor 4 (TLR4) ligand, with subsequent induction of potent tumor antigen-specific T cell immunity
We examined the contribution of host tumor immunity to the overall antitumor effects of Doxil® in a Colon 26 (C26) murine colon carcinoma model in immunocompetent or immunodeficient mice
Summary
Chemotherapy using cytotoxic chemicals to induce cell death, despite recent advances in alternative therapies, remains a frontline defense against malignant tumors Besides their direct cytotoxic effects against tumor cells, many chemotherapeutic agents have been reported to destroy various immune cell populations and, impair cell-mediated innate and adaptive antitumor immunity [1]. In addition to their direct cytotoxic effect, trigger a tumor-directed immune response or increase the vulnerability of tumor cells to immune attack [4,5,6]. Encapsulation of oxaliplatin (l-OHP) within PEGylated liposomes contributes to antitumor immunity by decreasing the number of immune suppressor cells, including TAMs, MDSCs and Tregs, which collectively suppress CD8+ T cell-mediated antitumor immunity [13]. We examined the contribution of host tumor immunity to the overall antitumor effects of Doxil® in a C26 murine colon carcinoma model in immunocompetent or immunodeficient mice
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
