Therapeutic Efficacy of Cancer Stem Cell Vaccines in the Adjuvant Setting
Yangyang HuLin LüYang XiaXin ChenAlfred E. ChangRobert E. HollingsworthElaine M. HurtJohn H. OwenJeffrey S. MoyerMark E. PrinceFu DaiYangyi BaoYi WangJoel WhitfieldJian‐Chuan XiaShiang HuangMax S. WichaQiao Li
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Abstract Dendritic cell (DC)-based vaccine strategies aimed at targeting cancer stem–like cells (CSC) may be most efficacious if deployed in the adjuvant setting. In this study, we offer preclinical evidence that this is the case for a CSC-DC vaccine as tested in murine models of SCC7 squamous cell cancer and D5 melanoma. Vaccination of mice with an ALDHhigh SCC7 CSC-DC vaccine after surgical excision of established SCC7 tumors reduced local tumor relapse and prolonged host survival. This effect was augmented significantly by simultaneous administration of anti-PD-L1, an immune checkpoint inhibitor. In the minimal disease setting of D5 melanoma, treatment of mice with ALDHhigh CSC-DC vaccination inhibited primary tumor growth, reduced spontaneous lung metastases, and increased host survival. In this setting, CCR10 and its ligands were downregulated on ALDHhigh D5 CSCs and in lung tissues, respectively, after vaccination with ALDHhigh D5 CSC-DC. RNAi-mediated attenuation of CCR10 blocked tumor cell migration in vitro and metastasis in vivo. T cells harvested from mice vaccinated with ALDHhigh D5 CSC-DC selectively killed ALDHhigh D5 CSCs, with additional evidence of humoral immunologic engagement and a reduction in ALDHhigh cells in residual tumors. Overall, our results offered a preclinical proof of concept for the use of ALDHhigh CSC-DC vaccines in the adjuvant setting to more effectively limit local tumor recurrence and spontaneous pulmonary metastasis, as compared with traditional DC vaccines, with increased host survival further accentuated by simultaneous PD-L1 blockade. Cancer Res; 76(16); 4661–72. ©2016 AACR.Keywords:
Cancer Immunotherapy
Nanoparticle-mediated cancer immunotherapy holds great promise, but more efforts are needed to obtain nanoformulations that result in a full scale activation of innate and adaptive immune components that specifically target the tumors. We generated a series of copper-doped TiO2 nanoparticles in order to tune the kinetics and full extent of Cu2+ ion release from the remnant TiO2 nanocrystals. Fine-tuning nanoparticle properties resulted in a formulation of 33% Cu-doped TiO2 which enabled short-lived hyperactivation of dendritic cells and hereby promoted immunotherapy. The nanoparticles result in highly efficient activation of dendritic cells ex vivo, which upon transplantation in tumor bearing mice, exceeded the therapeutic outcomes obtained with classically stimulated dendritic cells. Efficacious but simple nanomaterials that can promote dendritic cancer cell vaccination strategies open up new avenues for improved immunotherapy and human health.
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Cancer immunotherapy has been a favorable strategy for facilitating antitumor immunity. However, immune tolerance and an ultimate immunosuppressive tumor microenvironment (ITM) are primary obstacles. To achieve the goals of remodeling the ITM and promoting cancer immunotherapy, a versatile nanoparticle codelivering shikonin (SK) and PD-L1 knockdown siRNA (SK/siR-NPs) was reported. SK/siR-NPs are demonstrated to tellingly induce the immunogenic cell death (ICD) of tumor cells, leading to increased dendritic cell maturation. Moreover, SK/siR-NPs can cause an efficacious inhibition of PD-L1, leading to enhanced cytotoxic T lymphocyte response to tumor cells. Most importantly, SK/siR-NPs can restrain lactate production via the downregulation of pyruvate kinase-M2 (PKM2) and eventually repolarize tumor associated macrophages (TAMs) from the M2-subtype to M1-subtype states. Meanwhile, SK/siR-NPs suppress regulatory T lymphocytes to fight with the ITM. Overall, the developed co-delivery system presents a significant potential for cancer immunotherapy through simultaneously inducing ICD, repolarizing M2-TAMs, and relieving PD-L1 pathway-regulated immune tolerance.
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ObjectiveTo investigate whether immune adjuvant can enhance the immunity of dendritic cell vaccine against murine breast cancer. Methods4 groups of mice with tumor are injected saline, immume adjuvant, dendritic cell (DC) vaccine and DC vaccine coupled with immune vaccine, respectively. Tumor volume and weight are measured 21 d later.ResultsThe tumor size in the DC vaccine coupled with immune vaccine group was significantly small compared with control group (P=0.001) and the DC vaccine group (P=0.047).ConclusionImmune adjuvant can enhance the immunity of dendritic cell vaccine against murine breast cancer.
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Electrostatic interactions and phosphate exchange are the most important mechanisms for the adsorption of antigens onto aluminum-containing adjuvant. But the immunogenicity of the final vaccine is not proportional to the amount and the adsorption strength of antigens onto aluminum-containing adjuvant. The stability of aluminum adjuvant would be decreased while it is stored in room temperature. However, it does not affect immune enhancement activity. Usually, aluminum adjuvant should avoid exposure to elevated temperature in long time, and buffer salts such as phosphate could be used to protect vaccines containing aluminum adjuvant. Now the new formulation of aluminum-adjuvanted vaccine dry powder can increase the stability of vaccines. This review describes recent studies on the interaction between aluminum adjuvant and antigens, the stability of vaccines containing aluminum adjuvant and the development tendency of aluminum adjuvant.
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Nanoscience has long been lauded as a method through which tumor-associated barriers could be overcome. As successful as cancer immunotherapy has been, limitations associated with the tumor microenvironment or side effects of systemic treatment have become more apparent. In this Review, we seek to lay out the therapeutic challenges associated with the tumor microenvironment and the ways in which nanoscience is being applied to remodel the tumor microenvironment and increase the susceptibility of many cancer types to immunotherapy. We detail the nanomedicines on the cutting edge of cancer immunotherapy and how their interactions with the tumor microenvironment make them more effective than systemically administered immunotherapies.
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Dendritic cell (DC) based cancer immunotherapy aims at the activation of the immune system, and in particular tumor-specific cytotoxic T lymphocytes (CTLs) to eradicate the tumor. DCs represent a heterogeneous cell population, including conventional DCs (cDCs), consisting of cDC1s and cDC2s, plasmacytoid DCs (pDCs), and monocyte-derived DCs (moDCs). These DC subsets differ both in ontogeny and functional properties, such as the capacity to induce CD4+ and CD8+ T-cell activation. MoDCs are most frequently used for vaccination purposes, based on technical aspects such as availability and in vitro expansion. However, whether moDCs are superior over other DC subsets in inducing anti tumor immune responses, is unknown, and likely depends on tumor type and composition of the tumor microenvironment. In this review, we discuss cellular aspects essential for DC vaccination efficacy, and the most recent findings on different DC subsets that could be used for DC-based cancer immunotherapy. This can prove valuable for the future design of more effective DC vaccines by choosing different DC subsets, and sheds light on the working mechanism of DC immunotherapy.
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Recent progress in the approach towards immunotherapy of cancer consists in molecular definition of tumor antigens, new tools for phenotypical and functional characterization of tumor-specific effector cells and clinical use of novel adjuvants for optimal stimulation of a cancer-specific immune response such as dendritic cells. In spite of these advances and immunological as well as clinical responses in selected patients, mechanisms involved in dendritic-cell-based cancer immunotherapy are still poorly understood. Therefore, a standardized study design and small pilot trials are needed to explore open scientific questions in future clinical trials. This review focuses on the different parameters of dendritic cell biology relevant to cancer immunotherapy and on innovative approaches to hopefully enhance the efficacy of dendritic cell vaccination.
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