Combining Tumor Microenvironment Modulating Nanoparticles with Doxorubicin to Enhance Chemotherapeutic Efficacy and Boost Antitumor Immunity

Amini, Mohammad; Abbasi, Azhar Z.; Cai, Ping; Lip, HoYin; Gordijo, Claudia R.; Li, Jason; Chen, Branson; Zhang, Li; Rauth, Andrew M.; Wu, Xiao Yu

doi:10.1093/jnci/djy131

Cited by 54 publications

(43 citation statements)

References 52 publications

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“…Different from other chemotherapeutic agents that elicit nonimmunogenic apoptosis without an immunizing property, DOX treatment results in immunogenic cell death (ICD), which can elicit an effective anti-tumor immune response (Casares et al, 2005). Nevertheless, DOX, like other chemotherapeutic agents, also results in an immunosuppressive microenvironment that is favorable for tumor growth and progression, limiting and even removing cancer cell immune rejection (Amini et al, 2019). It is well known that both innate and adaptive immune responses play important roles in cancer progression and therapy (Karagiannis et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

RETRACTED: Berberine Maintains the Neutrophil N1 Phenotype to Reverse Cancer Cell Resistance to Doxorubicin

et al. 2020

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This study explores the contributions of neutrophils to chemotherapeutic resistance and berberine-regulated cancer cell sensitivity to doxorubicin (DOX). In vitro experiments, continuous DOX treatment led to the shift of HL-60 cells to N2 neutrophils and thus induced chemotherapeutic resistance. The combination treatment with DOX and 2 µM berberine resulted in the differentiation of HL-60 cells toward N1 and therefore stimulated HL-60 cell immune clearance. Berberine increased reactive oxygen species (ROS) and decreased autophagy and therefore induced apoptosis in HL-60-N2 cells with morphological changes, but had no effect on cell viability in HL-60-N1 cells. The neutrophil-regulating efficacy of berberine was confirmed in the urethane-induced lung carcinogenic model and H22 liver cancer allograft model. Furthermore, we found that DOX-derived neutrophils had high levels of CD133 and CD309 surface expression, which prevented both chemotherapeutic sensitivity and immune rejection by self-expression of PD-L1 and surface expression of PD-1 receptor on T cells, whereas berberine could downregulate CD133 and CD309 surface expression. Finally, berberine-relevant targets and pathways were evaluated. This study first suggests an important role of berberine in regulating neutrophil phenotypes to maintain cancer cell sensitivity to DOX.

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Section: Introductionmentioning

confidence: 99%

RETRACTED: Berberine Maintains the Neutrophil N1 Phenotype to Reverse Cancer Cell Resistance to Doxorubicin

et al. 2020

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“…Given that hypoxia modifiers and immune checkpoint inhibitors have been shown to exhibit a potential effect on breast cancer, we explored the potential role of a combined hypoxia and immune status classifier for TNBC in this study [57,58]. The use of a combined immune-hypoxia signature in a cross-cohort manner helped to develop a continuous index for comprehensive TME assessment.…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of a combined hypoxia and immune index for triple‐negative breast cancer

et al. 2020

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The interaction between hypoxia and immune status has been confirmed in various cancer settings, and corresponding treatments have been investigated. However, reliable biomarkers are needed for individual treatment, so we sought to develop a novel scoring system based on hypoxia and immune status. Prognostic hypoxia-immune status-related signatures of patients with triple-negative breast cancer (TNBC) were identified in The Cancer Genome Atlas (TCGA) (N = 158), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (N = 297), and GSE58812 (N = 107). LASSO Cox regression was used for model construction. Hypoxia and immune status expression profiles were analyzed, and infiltrating immune cells were compared. Quantitative real-time PCR (qRT-PCR) was used for validation in the Sun Yat-sen University Cancer Center (SYSUCC) cohort, and immunofluorescence was applied for the detection of hypoxia and immune markers in cancer tissues. Ten cross-cohort prognostic hypoxia-immune signatures were included to construct the comprehensive index of hypoxia and immune (CIHI) in the METABRIC cohort. Two subgroups of patients with distinct hypoxia-immune status conditions were identified using CIHI: hypoxia high /immune low and hypoxia low /immune high , with a significantly better overall survival (OS) rate in the latter (P < 0.01). The prognostic value of CIHI was further validated in the TCGA, GSE58812, and SYSUCC cohorts (P < 0.01).

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“…3g), but stronger type I-IFN production than MnCl 2 or Mn 2+ -PBS did (Extended Data Fig. 3h), probably due to the facilitated transportation into cells as nanoparticles 32, 33 . Compared to MnCl 2 , which disappeared within hours, MnJ had a much longer muscle retention time up to 8 days at the site of injection, similar to Mn 2+ -PBS particles (Extended Data Fig.…”

Section: Resultsmentioning

confidence: 93%

The Manganese Salt (MnJ) Functions as A Potent Universal Adjuvant

Zhang

Wang

Guan

et al. 2019

Preprint

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15Aluminum adjuvants have been used for a century in various vaccines due to its ability to 16 potentiate humoral immunity and safety records since 1920s. Manganese is an essential 17 micronutrient required for diverse biological activities in cells. We previously found that Mn 2+ is a 18 strong type I-interferon stimulator activating the cGAS-STING pathway. Herein we report that a 19 colloidal manganese salt (MnJ) is a potent adjuvant to induce both humoral and cellular immune 20 responses, particularly CTL activation. When administrated intranasally, MnJ was also a strong 21 mucosal adjuvant, inducing high levels of IgA antibodies. MnJ strongly promoted dendritic cell 22 maturation and antigen-specific T cell activation. Interestingly, IL-1/-18 induction and release by 23Mn 2+ -activated ASC-mediated inflammasomes were not observed. MnJ showed great adjuvant 24 effects to all tested antigens including inactivated viruses, recombinant proteins and peptides by 25 either intramuscular or intranasal immunization. These findings may have implications in 26 developing potent but safe Mn 2+ -containing vaccines. 27

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Combining Tumor Microenvironment Modulating Nanoparticles with Doxorubicin to Enhance Chemotherapeutic Efficacy and Boost Antitumor Immunity

Abstract: The clinically suitable PLMD NPs can effectively downregulate TME-associated drug resistance and immunosuppression. The combination therapy with PLMD NPs and DOX is a multimodal and translational treatment approach for enhancing chemotherapeutic efficacy and boosting antitumor immunity.

Cited by 54 publications

References 52 publications

RETRACTED: Berberine Maintains the Neutrophil N1 Phenotype to Reverse Cancer Cell Resistance to Doxorubicin

RETRACTED: Berberine Maintains the Neutrophil N1 Phenotype to Reverse Cancer Cell Resistance to Doxorubicin

Identification and validation of a combined hypoxia and immune index for triple‐negative breast cancer

The Manganese Salt (MnJ) Functions as A Potent Universal Adjuvant

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